Phosphodiesterase 4 inhibitors

ABSTRACT

PDE4 inhibition is achieved by novel compounds of the Formula I:  
                 
 
     wherein R 1  and R 2  are as defined herein.

[0001] This application claims benefit of U.S. Provisional applicationSerial No. 60/267,195, filed Feb. 8, 2001, and U.S. Provisionalapplication Serial No. 60/344,824, filed Jan. 7, 2002.

FIELD OF THE INVENTION

[0002] The present invention relates generally to the field ofphosphodiesterase 4 (PDE4) enzyme inhibition. More specifically thisinvention relates to selective PDE4 inhibition by novel adenine analogs,methods of preparing such compounds, compositions containing suchcompounds, and methods of use thereof.

BACKGROUND OF THE INVENTION

[0003] The cyclic nucleotide specific phosphodiesterases (PDEs)represent a family of enzymes that catalyze the hydrolysis of variouscyclic nucleoside monophosphates (including cAMP and cGMP). These cyclicnucleotides act as second messengers within cells, and as messengers,carry impulses from cell surface receptors having bound various hormonesand neurotransmitters. PDEs act to regulate the level of cyclicnucleotides within cells and maintain cyclic nucleotide homeostasis bydegrading such cyclic mononucleotides resulting in termination of theirmessenger role.

[0004] PDE enzymes can be grouped into eleven families according totheir specificity toward hydrolysis of cAMP or cGMP, their sensitivityto regulation by calcium, calmodulin or cGMP, and their selectiveinhibition by various compounds. For example, PDE 1 is stimulated byCa²⁺/calmodulin. PDE 2 is cGMP-dependent, and is found in the heart andadrenals. PDE 3 is cGMP-dependent, and inhibition of this enzyme createspositive inotropic activity. PDE 4 is cAMP specific, and its inhibitioncauses airway relaxation, antiinflammatory and antidepressant activity.PDE 5 appears to be important in regulating cGMP content in vascularsmooth muscle, and therefore PDE 5 inhibitors may have cardiovascularactivity. Since the PDEs possess distinct biochemical properties, it islikely that they are subject to a variety of different forms ofregulation.

[0005] PDE4 is distinguished by various kinetic properties including lowMichaelis constant for cAMP and sensitivity to certain drugs. The PDE4enzyme family consists of four genes, which produce 4 isoforms of thePDE4 enzyme designated PDE4A, PDE4B, PDE4C, and PDE4D [See: Wang et al.,Expression, Purification, and Characterization of human cAMP-SpecificPhosphodiesterase (PDE4) Subtypes A, B, C, and D, Biochem. Biophys. Res.Comm., 234, 320-324 (1997)] In addition, various splice variants of eachPDE4 isoform have been identified.

[0006] PDE4 isoenzymes are localized in the cytosol of cells and areunassociated with any known membranous structures. PDE4 isoenzymesspecifically inactivate cAMP by catalyzing its hydrolysis to adenosine5′-monophosphate (AMP). Regulation of cAMP activity is important in manybiological processes, including inflammation and memory. Inhibitors ofPDE4 isoenzymes such as rolipram, piclamilast, CDP-840 and ariflo arepowerful antiinflammatory agents and therefore may be useful in treatingdiseases where inflammation is problematic such as asthma or arthritis.Further, rolipram improves the cognitive performance of rats and mice inlearning paradigms.

[0007] In addition to such compounds as rolipram, xanthine derivativessuch as pentoxifylline, denbufylline, and theophylline inhibit PDE4 andhave received considerable attention of late for their cognitionenhancing effects. cAMP and cGMP are second messengers that mediatecellular responses to many different hormones and neurotransmitters.Thus, therapeutically significant effects may result from PDE inhibitionand the resulting increase in intracellular cAMP or cGMP in key cells,such as those located in the nervous system and elsewhere in the body.

[0008] Rolipram, previously in development as an anti-depressant,selectively inhibits the PDE4 enzyme and has become a standard agent inthe classification of PDE enzyme subtypes. Early work in the PDE4 fieldfocused on depression and inflammation, and has subsequently beenextended to include indications such as dementia. [see “The PDE IVFamily Of Calcium-Phosphodiesterases Enzymes,” John A. Lowe, III, etal., Drugs of the Future 1992, 17(9):799-807 for a general review).Further clinical developments of rolipram and other first-generationPDE4 inhibitors were terminated due to the side effect profile of thesecompounds. The primary side effect in primates is emesis, while theprimary side effects in rodents are testicular degranulation, weakeningof vascular smooth muscle, psychotrophic effects, increased gastric acidsecretion and stomach erosion.

SUMMARY OF THE INVENTION

[0009] The present invention relates to novel adenine compounds thatinhibit PDE4 enzymes, and especially have improved side effect profiles,e.g., are relatively non-emetic, (e.g., as compared to the previouslydiscussed prior art compounds). In particular, the present inventionrelates to novel 9-substituted-2-trifluoromethyladenine compounds thatpossess PDE4 inhibitory activity. Preferably, the compounds selectivelyinhibit PDE4 enzymes. The compounds of this invention at the same timefacilitate entry into cells, especially cells of the nervous system.

[0010] Still further, the present invention provides methods forsynthesizing compounds with such activity and selectivity as well asmethods of (and corresponding pharmaceutical compositions for) treatinga patient, e.g., mammals, including humans, requiring PDE inhibition,especially PDE4 inhibition, for a disease state that involves elevatedintracellular PDE 4 levels or decreased cAMP levels, e.g., involvingneurological syndromes, especially those states associated with memoryimpairment, most especially long term memory impairment, as where suchmemory impairment is due in part to catabolism of intracellular cAMPlevels by PDE 4 enzymes, or where such memory impairment may be improvedby effectively inhibiting PDE4 enzyme activity.

[0011] In a preferred aspect, the compounds of the invention improvesuch diseases by inhibiting PDE4 enzymes at doses which do not induceemesis.

[0012] Upon further study of the specification and appended claims,further aspects, objects and advantages of this invention will becomeapparent to those skilled in the art.

[0013] The present invention includes compounds of Formula I:

[0014] wherein,

[0015] R¹ is H,

[0016] alkyl having 1 to 5 carbon atoms, which is unsustituted orsubstituted one or more times by halogen, hydroxy, or combinationsthereof, and wherein a —CH₂— group can be optionally replaced by —O—,—S—, or —NH—,

[0017] cycloalkyl having 3 to 6 carbon atoms, or

[0018] cycloalkylalkyl having 4 to 7 C atoms;

[0019] R² is alkyl having 1 to 12 carbon atoms, which is unsubstitutedor substituted one or more times by halogen, hydroxy, cyano orcombinations thereof, wherein one or more —CH₂— groups is eachindependently optionally replaced by —O—, —S—, or —NH—, and whereinoptionally one or more —CH₂CH₂— groups is replaced in each case by—CH═CH— or —C≡C—,

[0020] alkyl ether having 3 to 12 carbon atoms,

[0021] cycloalkyl having 3 to 12 carbon atoms, which is unsubstituted orsubstituted one or more times by halogen, C₁₋₄ alkyl, halogenated C₁₋₄alkyl, C₁₋₄ alkoxy, cyano or combinations thereof,

[0022] cycloalkylalkyl having 4 to 12 C atoms, which is unsubstituted orsubstituted one or more times by C₁₋₄ alkyl, halogenated C₁₋₄ alkyl,C₁₋₄ alkoxy, cyano, halogen, or combinations thereof,

[0023] aryl having 6 to 14 carbon atoms, which is unsubstituted orsubstituted one or more times by halogen, C₁₋₄ alkyl, halogenated C₁₋₄alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, nitro,methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy,cyano, hydroxamic acid, carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof,

[0024] arylalkyl having 7 to 16 carbon atoms, which is unsubstituted orsubstituted one or more times by halogen, C₁₋₄ alkyl, halogenated C₁₋₄alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, nitro,methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy,cyano, hydroxamic acid, carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof,

[0025] heteroaryl having 5 to 10 ring atoms in which at least 1 ringatom is a heteroatom, which is unsubstituted or substituted one or moretimes by halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy,C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl, nitro,oxo, amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy,alkoxycarbonyl, hydroxamic acid, carboxamide, C₁₋₄-alkylthio,C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, or combinations thereof,

[0026] heteroarylalkyl wherein the heteroaryl portion has 5 to 10 ringatoms in which at least 1 ring atom is a heteroatom and the alkylportion has 1 to 3 carbon atoms, the heteroaryl portion is unsubstitutedor is substituted one or more times in by halogen, aryl, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy,cyano, trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid,carboxamide, C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl,or combinations thereof,

[0027] heterocycle having 5 to 10 ring atoms in which at least 1 ringatom is a heteroatom, which is unsubstituted or is substituted one ormore times by halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl,hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl,nitro, oxo, amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy,alkoxycarbonyl, or combinations thereof (e.g., piperidinyl,imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl,piperazinyl, and indolinyl),

[0028] heterocycle-alkyl wherein the heterocycle portion has 5 to 10ring atoms in which at least 1 ring atom is a heteroatom and the alkylportion has 1 to 3 carbon atoms, the heterocycle portion is nonarmoaticand is unsubstituted or is substituted one or more times in the byhalogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy, Cl ₄-alkoxy,halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, Cl₄-alkylamino, di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, orcombinations thereof (e.g., piperidinyl-ethyl and pyrrolinyl-methyl), or

[0029] carbocycle which is nonaromatic, monocyclic or bicyclic, grouphaving 5 to 14 carbon atoms, which is unsubstituted or is substitutedone or more times in the by halogen, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl,hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, nitro, methylmedioxy,ethylenedioxy, amino, C₁₋₄ alkylamino, di-C₁₋₄-alkylamino,C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy, cyano, hydroxamic acid,carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl, C₁₋₄-alkylthio,C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, or combinationsthereof; and

[0030] pharmaceutically acceptable salts thereof,

[0031] with the provisos that:

[0032] (a) when R¹ is methyl, then R² is not arylalkyl, heteroarylalkyl,2-(1,2,3,4-tetrahydro)quinolinyl-methyl, methyl or 2-butyl;

[0033] (b) when R¹ is cyclopropyl, R² is not 4-methylbenzyl;

[0034] (c) when R¹ is ethyl, then R² is not ethyl, 3-aminobenzyl,2-thienylmethyl, 3-thienylmethyl, or 2-pyridylmethyl;

[0035] (d) when R¹ is cyclopropyl, then R² is not cyclopropylmethyl;

[0036] (e) when R¹ is H, then R² is not methyl, ethyl, benzyl,4-methylbenzyl, or substituted tetrahydrofuranyl;

[0037] (f) when R¹ is methoxyethyl, then R² is not benzyl,3-dimethylaminobenzyl, or 3-thienylmethyl;

[0038] (g) when R¹ is iso-butyl, then R² is not benzyl; and

[0039] (h) when R¹ is n-butyl, then R² is not n-butyl.

[0040] According to a further aspect of the invention there is provideda genus according to formula I wherein when R¹ is methyl, R² is notarylalkyl, heteroarylalkyl, 2-(1,2,3,4-tetrahydro)quinolinyl-methyl orC₁₋₅-alkyl.

[0041] According to a further aspect of the invention there is provideda genus according to formula I wherein when R¹ is methyl, R² is notarylalkyl, heteroarylalkyl, heterocycle-alkyl or C₁₋₅-alkyl.

[0042] According to a further aspect of the invention there is provideda genus according to formula I wherein when R¹ is cyclopropyl, R² is notarylalkyl.

[0043] According to a further aspect of the invention there is provideda genus according to formula I wherein when R¹ is ethyl, R² is notarylalkyl, heteroarylalkyl, or C₁₋₃-alkyl.

[0044] According to a further aspect of the invention there is provideda genus according to formula I wherein when R¹ is cyclopropyl, R² is notcycloalkylalkyl.

[0045] According to a further aspect of the invention there is provideda genus according to formula I wherein when R¹ is H, R² is notarylalkyl, heterocycle or C₁₋₃-alkyl.

[0046] According to a further aspect of the invention there is provideda genus according to formula I wherein when R¹ is methoxyethyl, R² isnot arylalkyl or heteroarylalkyl.

[0047] According to a further aspect of the invention there is provideda genus according to formula I wherein when R¹ is a butyl group, R² isnot arylalkyl or C₁₋₅-alkyl.

[0048] According to a preferred aspect of the invention there isprovided a genus of novel compounds according to formula II

[0049] wherein

[0050] R¹′ is methyl, ethyl, or cyclopropyl; and

[0051] R²′ is cycloalkyl having 3 to 12 carbon atoms, which isunsubstituted or substituted one or more times by halogen, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano or combinations thereof,

[0052] aryl having 6 to 14 carbon atoms, which is unsubstituted orsubstituted one or more times by halogen, C₁₋₄ alkyl, halogenated C₁₋₄alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, nitro,methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy,cyano, hydroxamic acid, carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof,

[0053] heteroaryl having 5 to 10 ring atoms in which at least 1 ringatom is a heteroatom, which is unsubstituted or substituted one or moretimes by halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy,C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl, nitro,oxo, amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy,alkoxycarbonyl, hydroxamic acid, carboxamide, C₁₋₄-alkylthio,C₁₋₄-,alkylsulphinyl, C₁₋₄-alkylsulphonyl, or combinations thereof,

[0054] heterocycle having 5 to 10 ring atoms in which at least 1 ringatom is a heteroatom, which is unsubstituted or is substituted one ormore times in the by halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl,hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl,nitro, oxo, amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy,alkoxycarbonyl, or combinations thereof (e.g., piperidinyl,imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl,piperazinyl, and indolinyl), or

[0055] carbocycle which is nonaromatic, monocyclic or bicyclic, grouphaving 5 to 14 carbon atoms, which is unsubstituted or is substitutedone or more times in the by halogen, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl,hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, nitro, methylenedioxy,ethylenedioxy, amino, C₁₋₄ alkylamino, di-C₁₋₄-alkylamino,C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy, cyano, hydroxamic acid,carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl, C₁₋₄-alkylthio,C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, or combinationsthereof; and

[0056] pharmaceutically acceptable salts thereof.

[0057] According to a further aspect of the invention there is provideda genus of novel compounds according to the Formula III:

[0058] wherein

[0059] R¹″ is H,

[0060] alkyl having 1 to 5 carbon atoms,

[0061] alkyl having 1 to 5 carbon atoms which is substituted one or moretimes by halogen, hydroxy, oxo, cyano or combinations thereof,

[0062] cycloalkyl having 3 to 6 carbon atoms,

[0063] cycloalkyl having 3 to 6 carbon atoms, which is substituted oneor more times by halogen, alkyl, oxo or combinations thereof,

[0064] cycloalkylalkyl having 4 to 7 C atoms,

[0065] cycloalkylalkyl having 4 to 7 C atoms, which is substituted oneor more times by C₁₋₄ alkyl, halogen, halogenated C₁₋₄ alkyl, orcombinations thereof,

[0066] R²″ is alkyl having 1 to 12 carbon atoms,

[0067] alkyl having 1 to 12 carbon atoms which is substituted one ormore times by halogen, hydroxy, oxo, cyano or combinations thereof,

[0068] alkyl ether having 3 to 12 carbon atoms,

[0069] cycloalkyl having 3 to 12 carbon atoms,

[0070] cycloalkyl having 3 to 12 carbon atoms which is substituted oneor more times by halogen, C₁₋₄ alkyl, oxo or combinations thereof,

[0071] cycloalkylalkyl having 4 to 12 C atoms,

[0072] cycloalkylalkyl having 4 to 12 C atoms, which is substituted oneor more times by C₁₋₄ alkyl, halogen, halogenated C₁₋₄ alkyl, orcombinations thereof,

[0073] aryl having 6 to 10 carbon atoms,

[0074] aryl having 6 to 10 carbon atoms which is substituted one or moretimes by halogen, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy,C₁₋₄-alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄alkylamino, di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy,carboxy, cyano, C₂₋₄, acyl, C₂₋₄-alkoxycarbonyl, C₁₋₄-alkylthio,C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, , or combinationsthereof,

[0075] arylalkyl having 7 to 16 carbon atoms,

[0076] arylalkyl having 7 to 16 carbon atoms which is substituted one ormore times by halogen, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy,C₁₋₄-alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄alkylamino, di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy,carboxy, cyano, C₂₋₄, acyl, C₂₋₄-alkoxycarbonyl, C₁₋₄-alkylthio,C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, or combinationsthereof,

[0077] heteroaryl having 5 to 10 ring atoms in which at least 1 ringatom is a heteroatom,

[0078] substituted heteroaryl having 5 to 10 ring atoms, in which atleast 1 ring atom is a heteroatom, which is substituted one or moretimes by halogen, aryl, C₁₋₄-alkyl, C₁₋₄-alkoxy, cyano, trifluoromethyl,nitro, oxo, amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino or combinationsthereof,

[0079] heteroarylalkyl having 5 to 10 ring atoms in which at least 1ring atom is a heteroatom, or

[0080] substituted heteroarylalkyl having 5 to 10 ring atoms in which atleast 1 ring atom is a heteroatom and which is substituted one or moretimes in the heteroaryl portion by halogen, aryl, C₁₋₄-alkyl,C₁₋₄-alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,di-C₁₋₄-alkylamino or combinations thereof and/or substituted in thealkyl portion by halogen, oxo, cyano, or combinations thereof; and

[0081] pharmaceutically acceptable salts thereof,

[0082] with the provisos that

[0083] (a) when R¹″ is methyl, then R²″ is not arylalkyl,heteroarylalkyl, methyl or 2-butyl,

[0084] (b) when R¹″ is cyclopropyl, R²″ is not 4-methylbenzyl,

[0085] (c) when R¹″ is ethyl, then R²″ is not ethyl, and

[0086] (d) when R¹″ is cyclopropyl, then R²″ is not cyclopropylmethyl.

[0087] In accordance with a further aspect of the invention, there isprovided a genus of formula III in which R¹″ and R²″ are in accordancewith the following subformulas:

[0088] IIIa R¹″ is cyclopropyl; and

[0089] R²″ is cycloalkyl.

[0090] IIIb R¹″ is methyl; and

[0091] R²″ is cycloalkyl.

[0092] IIIc R¹″ is methyl, ethyl, cyclopropyl; and

[0093] R²″ is phenyl or substituted phenyl.

[0094] IIId R¹″ is methyl, ethyl, cyclopropyl; and

[0095] R²″ is heteroaryl or substituted heteroaryl.

[0096] The compounds of the present invention are effective ininhibiting, or modulating the activity of PDE4 in animals, e.g.,mammals, especially humans. These compounds exhibit neurologicalactivity, especially where such activity affects cognition, includinglong term memory. These compounds will also be effective in treatingdiseases where decreased cAMP levels are involved. This includes but isnot limited to inflammatory diseases. These compounds may also functionas antidepressants, or be useful in treating cognitive and negativesymptoms of schizophrenia.

[0097] In accordance with the method aspect of the invention, there isprovided a method of treating a patient (e.g., a mammal such as a human)suffering from a disease state (e.g., memory impairment, inflammatorydisesases, depression, etc.) involving decreased cAMP levels and/orincreased intracellular PDE4 levels, comprising administering to thepatient a compound according to formula I^(a):

[0098] wherein,

[0099] R^(1a) is H,

[0100] alkyl having 1 to 5 carbon atoms, which is unsustituted orsubstituted one or more times by halogen, hydroxy, or combinationsthereof, and wherein a —CH₂— group can be optionally replaced by —O—,—S—, or —NH—,

[0101] cycloalkyl having 3 to 6 carbon atoms, or

[0102] cycloalkylalkyl having 4 to 7 C atoms;

[0103] R^(2a) is alkyl having 1 to 12 carbon atoms, which isunsubstituted or substituted one or more times by halogen, hydroxy,cyano or combinations thereof, wherein one or more —CH₂— groups is eachindependently optionally replaced by —O—, —S—, or —NH—, and whereinoptionally one or more —CH₂CH₂— groups is replaced in each case by—CH═CH— or —C≡C—

[0104] alkyl ether having 3 to 12 carbon atoms,

[0105] cycloalkyl having 3 to 12 carbon atoms, which is unsubstituted orsubstituted one or more times by halogen, C₁₋₄ alkyl, halogenated C₁₋₄alkyl, C₁₋₄ alkoxy, cyano or combinations thereof,

[0106] cycloalkylalkyl having 4 to 12 C atoms, which is unsubstituted orsubstituted one or more times by C₁₋₄ alkyl, halogenated C₁₋₄ alkyl,C₁₋₄ alkoxy, cyano, halogen, or combinations thereof,

[0107] aryl having 6 to 14 carbon atoms, which is unsubstituted orsubstituted one or more times by halogen, C₁₋₄ alkyl, halogenated C₁₋₄alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, nitro,methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy,cyano, hydroxamic acid, carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof,

[0108] arylalkyl having 7 to 16 carbon atoms, which is unsubstituted orsubstituted one or more times by halogen, C₁₋₄ alkyl, halogenated C₁₋₄alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, nitro,methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy,cyano, hydroxamic acid, carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof,

[0109] heteroaryl having 5 to 10 ring atoms in which at least 1 ringatom is a heteroatom, which is unsubstituted or substituted one or moretimes by halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy,C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl, nitro,oxo, amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy,alkoxycarbonyl, hydroxamic acid, carboxamide, C₁₋₄-alkylthio,C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, or combinations thereof,

[0110] heteroarylalkyl wherein the heteroaryl portion has 5 to 10 ringatoms in which at least 1 ring atom is a heteroatom and the alkylportion has 1 to 3 carbon atoms, the heteroaryl portion is unsubstitutedor is substituted one or more times in by halogen, aryl, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy,cyano, trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid,carboxamide, C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl,or combinations thereof,

[0111] heterocycle having 5 to 10 ring atoms in which at least 1 ringatom is a heteroatom, which is unsubstituted or is substituted one ormore times in the by halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl,hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl,nitro, oxo, amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy,alkoxycarbonyl, or combinations thereof (e.g., piperidinyl,imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl,piperazinyl, and indolinyl),

[0112] heterocycle-alkyl wherein the heterocycle portion has 5 to 10ring atoms in which at least 1 ring atom is a heteroatom and the alkylportion has 1 to 3 carbon atoms, the heterocycle portion is nonarmoaticand is unsubstituted or is substituted one or more times in the byhalogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy,halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl, nitro, oxo, amino,C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, orcombinations thereof (e.g., piperidinyl-ethyl and pyrrolinyl-methyl), or

[0113] carbocycle which is nonaromatic, monocyclic or bicyclic, grouphaving 5 to 14 carbon atoms, which is unsubstituted or is substitutedone or more times in the by halogen, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl,hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, nitro, methylenedioxy,ethylenedioxy, amino, C₁₋₄ alkylamino, di-C₁₋₄-alkylamino,C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy, cyano, hydroxamic acid,carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl, C₁₋₄-alkylthio,C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, or combinationsthereof; and

[0114] pharmaceutically acceptable salts thereof,

[0115] with the provisos that:

[0116] (a) when R^(1a) is methyl, then R^(2a) is not arylalkyl,heteroarylalkyl, 2-(1,2,3,4-tetrahydro)quinolinyl-methyl, methyl or2-butyl;

[0117] (b) when R^(1a) is cyclopropyl, R^(2a) is not 4-methylbenzyl;

[0118] (c) when R^(1a) is ethyl, then R^(2a) is not ethyl,3-aminobenzyl, 2-thienylmethyl, 3-thienylmethyl, or 2-pyridylmethyl;

[0119] (d) when R^(1a) is cyclopropyl, then R^(2a) is notcyclopropylmethyl;

[0120] (e) when R^(1a) is H, then R^(2a) is not methyl, ethyl, benzyl,4-methylbenzyl, or substituted tetrahydrofuranyl;

[0121] (f) when R^(1a) is methoxyethyl, then R^(2a) is not benzyl,3-dimethylaminobenzyl, or 3-thienyhnethyl;

[0122] (g) when R^(1a) is iso-butyl, then R^(2a) is not benzyl; and

[0123] (h) when R^(1a) is n-butyl, then R^(2a) is not n-butyl.

[0124] In accordance with the method aspect of the invention, there isprovided a method of treating a patient (e.g., a mammal such as a human)suffering from a disease state (e.g., memory impairment) involvingdecreased cAMP levels and/or increased intracellular PDE4 levels,comprising administering to the patient a compound according to formulaI^(b):

[0125] wherein,

[0126] R^(1b) is H,

[0127] alkyl having 1 to 5 carbon atoms, which is unsustituted orsubstituted one or more times by halogen, hydroxy, or combinationsthereof, and wherein a —CH₂— group can be optionally replaced by —O—,—S—, or —NH—,

[0128] cycloalkyl having 3 to 6 carbon atoms, or

[0129] cycloalkylalkyl having 4 to 7 C atoms;

[0130] R^(2b) is alkyl having 1 to 12 carbon atoms, which isunsubstituted or substituted one or more times by halogen, hydroxy,cyano or combinations thereof, wherein one or more —CH₂— groups is eachindependently optionally replaced by —O—, —S—, or —NH—, and whereinoptionally one or more —CH₂CH₂— groups is replaced in each case by—CH═CH— or —C≡C—

[0131] alkyl ether having 3 to 12 carbon atoms,

[0132] cycloalkyl having 3 to 12 carbon atoms, which is unsubstituted orsubstituted one or more times by halogen, C₁₋₄ alkyl, halogenated C₁₋₄alkyl, C₁₋₄ alkoxy, cyano or combinations thereof,

[0133] cycloalkylalkyl having 4 to 12 C atoms, which is unsubstituted orsubstituted one or more times by C₁₋₄ alkyl, halogenated C₁₋₄ alkyl,C₁₋₄ alkoxy, cyano, halogen, or combinations thereof,

[0134] aryl having 6 to 14 carbon atoms, which is unsubstituted orsubstituted one or more times by halogen, C₁₋₄ alkyl, halogenated C₁₋₄alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, nitro,methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy,cyano, hydroxamic acid, carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof,

[0135] arylalkyl having 7 to 16 carbon atoms, which is unsubstituted orsubstituted one or more times by halogen, C₁₋₄ alkyl, halogenated C₁₋₄alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, nitro,methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy,cyano, hydroxamic acid, carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof,

[0136] heteroaryl having 5 to 10 ring atoms in which at least 1 ringatom is a heteroatom, which is unsubstituted or substituted one or moretimes by halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy,C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl, nitro,oxo, amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy,alkoxycarbonyl, hydroxamic acid, carboxamide, C₁₋₄-alkylthio,C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, or combinations thereof,

[0137] heteroarylalkyl wherein the heteroaryl portion has 5 to 10 ringatoms in which at least 1 ring atom is a heteroatom and the alkylportion has 1 to 3 carbon atoms, the heteroaryl portion is unsubstitutedor is substituted one or more times in by halogen, aryl, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy,cyano, trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid,carboxamide, C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl,or combinations thereof,

[0138] heterocycle having 5 to 10 ring atoms in which at least 1 ringatom is a heteroatom, which is unsubstituted or is substituted one ormore times in the by halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl,hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl,nitro, oxo, amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy,alkoxycarbonyl, or combinations thereof (e.g., piperidinyl,imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl,piperazinyl, and indolinyl),

[0139] heterocycle-alkyl wherein the heterocycle portion has 5 to 10ring atoms in which at least 1 ring atom is a heteroatom and the alkylportion has 1 to 3 carbon atoms, the heterocycle portion is nonarmoaticand is unsubstituted or is substituted one or more times in the byhalogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy,halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl, nitro, oxo, amino,C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, orcombinations thereof (e.g., piperidinyl-ethyl and pyrrolinyl-methyl), or

[0140] carbocycle which is nonaromatic, monocyclic or bicyclic, grouphaving 5 to 14 carbon atoms, which is unsubstituted or is substitutedone or more times in the by halogen, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl,hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, nitro, methylenedioxy,ethylenedioxy, amino, C₁₋₄ alkylamino, di-C₁₋₄-alkylamino,C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy, cyano, hydroxamic acid,carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl, C₁₋₄alkylthio,C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, or combinationsthereof; and

[0141] pharmaceutically acceptable salts thereof,

[0142] with the provisos that when R^(1b) is methyl, then R^(2b) is notarylalkyl, methyl or 2-butyl, and when R^(1b) is H, then R^(2b) is notbenzyl.

[0143] In accordance with a further method aspect of the invention,there is provided a method of treating a patient (e.g., a mammal such asa human) suffering from a disease state (e.g., memory impairment)involving decreased cAMP levels and/or increased intracellular PDE4levels, comprising administering to the patient a compound according toformula I^(c):

[0144] wherein,

[0145] R^(1c) is H,

[0146] alkyl having 1 to 5 carbon atoms, which is unsustituted orsubstituted one or more times by halogen, hydroxy, or combinationsthereof, and wherein a —CH₂— group can be optionally replaced by —O—,—S—, or —NH—,

[0147] cycloalkyl having 3 to 6 carbon atoms, or

[0148] cycloalkylalkyl having 4 to 7 C atoms;

[0149] R^(2c) is alkyl having 1 to 12 carbon atoms, which isunsubstituted or substituted one or more times by halogen, hydroxy,cyano or combinations thereof, wherein one or more —CH₂— groups is eachindependently optionally replaced by —O—, —S—, or —NH—, and whereinoptionally one or more —CH₂CH₂— groups is replaced in each case by—CH═CH— or —C≡C—

[0150] alkyl ether having 3 to 12 carbon atoms,

[0151] cycloalkyl having 3 to 12 carbon atoms, which is unsubstituted orsubstituted one or more times by halogen, C₁₋₄ alkyl, halogenated C₁₋₄alkyl, C₁₋₄ alkoxy, cyano or combinations thereof,

[0152] cycloalkylalkyl having 4 to 12 C atoms, which is unsubstituted orsubstituted one or more times by C₁₋₄ alkyl, halogenated C₁₋₄ alkyl,C₁₋₄ alkoxy, cyano, halogen, or combinations thereof,

[0153] aryl having 6 to 14 carbon atoms, which is unsubstituted orsubstituted one or more times by halogen, C₁₋₄ alkyl, halogenated C₁₋₄alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, nitro,methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy,cyano, hydroxamic acid, carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof,

[0154] arylalkyl having 7 to 16 carbon atoms, which is unsubstituted orsubstituted one or more times by halogen, C₁₋₄ alkyl, halogenated C₁₋₄alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, nitro,methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy,cyano, hydroxamic acid, carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof,

[0155] heteroaryl having 5 to 10 ring atoms in which at least 1 ringatom is a heteroatom, which is unsubstituted or substituted one or moretimes by halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy,C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl, nitro,oxo, amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy,alkoxycarbonyl, hydroxamic acid, carboxamide, C₁₋₄-alkylthio,C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, or combinations thereof,

[0156] heteroarylalkyl wherein the heteroaryl portion has 5 to 10 ringatoms in which at least 1 ring atom is a heteroatom and the alkylportion has 1 to 3 carbon atoms, the heteroaryl portion is unsubstitutedor is substituted one or more times in by halogen, aryl, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy,cyano, trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid,carboxamide, C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl,or combinations thereof,

[0157] heterocycle having 5 to 10 ring atoms in which at least 1 ringatom is a heteroatom, which is unsubstituted or is substituted one ormore times in the by halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl,hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl,nitro, oxo, amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy,alkoxycarbonyl, or combinations thereof (e.g., piperidinyl,imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl,piperazinyl, and indolinyl),

[0158] heterocycle-alkyl wherein the heterocycle portion has 5 to 10ring atoms in which at least 1 ring atom is a heteroatom and the alkylportion has 1 to 3 carbon atoms, the heterocycle portion is nonarmoaticand is unsubstituted or is substituted one or more times in the byhalogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy,halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl, nitro, oxo, amino,C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, orcombinations thereof (e.g., piperidinyl-ethyl and pyrrolinyl-methyl), or

[0159] carbocycle which is nonaromatic, monocyclic or bicyclic, grouphaving 5 to 14 carbon atoms, which is unsubstituted or is substitutedone or more times in the by halogen, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl,hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, nitro, methylenedioxy,ethylenedioxy, amino, C₁₋₄ alkylamino, di-C₁₋₄-alkylamino,C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy, cyano, hydroxamic acid,carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl, C₁₋₄-alkylthio,C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, or combinationsthereof, and

[0160] pharmaceutically acceptable salts thereof,

[0161] with the proviso that said compound is not6-methylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine.

[0162] In accordance with a further method aspect of the invention,there is provided a method of treating a patient (e.g., a mammal such asa human) suffering from a disease state (e.g., memory impairment)involving decreased cAMP levels and/or increased intracellular PDE4levels, comprising administering to the patient a compound according toformula II

[0163] wherein

[0164] R¹′ is methyl, ethyl, or cyclopropyl; and

[0165] R²′ is cycloalkyl having 3 to 12 carbon atoms, which isunsubstituted or substituted one or more times by halogen, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano or combinations thereof,

[0166] aryl having 6 to 14 carbon atoms, which is unsubstituted orsubstituted one or more times by halogen, C₁₋₄alkyl, halogenated C₁₋₄alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, nitro,methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy,cyano, hydroxamic acid, carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof,

[0167] heteroaryl having 5 to 10 ring atoms in which at least 1 ringatom is a heteroatom, which is unsubstituted or substituted one or moretimes by halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy,C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl, nitro,oxo, amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy,alkoxycarbonyl, hydroxamic acid, carboxamide, C₁₋₄-alkylthio,C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, or combinations thereof,

[0168] heterocycle having 5 to 10 ring atoms in which at least 1 ringatom is a heteroatom, which is unsubstituted or is substituted one ormore times in the by halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl,hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl,nitro, oxo, amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy,alkoxycarbonyl, or combinations thereof (e.g., piperidinyl,imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl,piperazinyl, and indolinyl), or

[0169] carbocycle which is nonaromatic, monocyclic or bicyclic, grouphaving 5 to 14 carbon atoms, which is unsubstituted or is substitutedone or more times in the by halogen, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl,hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, nitro, methylenedioxy,ethylenedioxy, amino, C₁₋₄ alkylamino, di-C₁₋₄-alkylamino,C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy, cyano, hydroxamic acid,carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl, C₁₋₄-alkylthio,C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, or combinationsthereof; and

[0170] pharmaceutically acceptable salts thereof.

[0171] In accordance with a further method aspect of the invention,there is provided a method of treating a patient (e.g., a mammal such asa human) suffering from a disease state (e.g., memory impairment)involving decreased cAMP levels and/or increased intracellular PDE4levels, comprising administering to the patient a compound according toformula III^(a):

[0172] wherein,

[0173] R¹′″ is H,

[0174] alkyl having 1 to 5 carbon atoms, which is unsustituted or issubstituted one or more times by halogen, hydroxy, oxo, cyano orcombinations thereof,

[0175] cycloalkyl having 3 to 6 carbon atoms, which is unsubstituted oris substituted one or more times by halogen, alkyl, oxo or combinationsthereof, or

[0176] cycloalkylalkyl having 4 to 7 C atoms, which is unsubstituted oris substituted one or more times by C₁₋₄ alkyl, halogen, halogenatedC₁₋₄ alkyl, or combinations thereof; and

[0177] R²′″ is alkyl having 1 to 12 carbon atoms, which is unsubstitutedor which is substituted one or more times by halogen, hydroxy, oxo,cyano or combinations thereof,

[0178] alkyl ether having 3 to 12 carbon atoms,

[0179] cycloalkyl having 3 to 12 carbon atoms, which is unsubstituted orwhich is substituted one or more times by halogen, C₁₋₄ alkyl, oxo orcombinations thereof,

[0180] cycloalkylalkyl having 4 to 12 C atoms, which is unsubstituted oris substituted one or more times by C₁₋₄ alkyl, halogen, halogenatedC₁₋₄ alkyl, or combinations thereof,

[0181] aryl having 6 to 10 carbon atoms, which is unsubstituted or issubstituted one or more times by halogen, C₁₋₄ alkyl, halogenated C₁₋₄alkyl, hydroxy, C₁₋₄-alkoxy, nitro, methylenedioxy, ethylenedioxy,amino, C₁₋₄ alkylamino, di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl,C₁₋₄-hydroxyalkoxy, carboxy, cyano, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof,

[0182] arylalkyl having 7 to 16 carbon atoms, which is unsubstituted oris substituted one or more times by halogen, C₁₋₄ alkyl, halogenatedC₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, nitro, methylenedioxy, ethylenedioxy,amino, C₁₋₄ alkylamino, di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl,C₁₋₄-hydroxyalkoxy, carboxy, cyano, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof,

[0183] heteroaryl having 5 to 10 ring atoms in which at least 1 ringatom is a heteroatom, substituted heteroaryl having 5 to 10 ring atoms,in which at least 1 ring atom is a heteroatom, which is substituted oneor more times by halogen, aryl, C₁₋₄-alkyl, C₁₋₄-alkoxy, cyano,trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylaminoor combinations thereof, or

[0184] heteroarylalkyl having 5 to 10 ring atoms in which at least 1ring atom is a heteroatom, which is unsubstituted or is substituted oneor more times in the heteroaryl portion by halogen, aryl, C₁₋₄-alkyl,C₁₋₄-alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,di-C₁₋₄-alkylamino or combinations thereof and/or substituted in thealkyl portion by halogen, oxo, cyano, or combinations thereof; and

[0185] pharmaceutically acceptable salts thereof,

[0186] with the proviso that

[0187] (a) when R¹′″ is methyl, then R²′″ is not arylalkyl,heteroarylalkyl, methyl or 2-butyl.

[0188] In formula III^(a), R¹′″ is preferably methyl, ethyl orcyclopropyl.

[0189] Assays for determining PDE inhibiting activity as well asselectivity of PDE 4 inhibiting activity and selectivity of inhibitingPDE 4 isoenzymes are known within the art. See, e.g., U.S. Pat. No.6,136,821, the disclosure of which is incorporated herein by reference.

[0190] Halogen herein refers to F, Cl, Br, and I. Preferred halogens areF and Cl.

[0191] Alkyl, as a group or substituent per se or as part of a group orsubstituent (e.g., alkylamino, trialkylsilyloxy, aminoalkyl,hydroxyalkyl), means a straight-chain or branched-chain aliphatichydrocarbon radical having 1 to 12 carbon atoms, preferably 1 to 8carbon atoms, especially 1 to 4 carbon atoms.

[0192] Alkyl radicals for R¹ have up to 5 carbon atoms, preferably 1 to4 carbon atoms, especially 1 to 3 carbon atoms. Suitable alkyl groupsfor R¹ include methyl, ethyl, propyl, isopropyl, butyl, isopropyl andpentyl. Other examples of suitable alkyl groups for R¹ include 1-, 2- or3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl and 1-ethylpropyl.

[0193] Alkyl radicals for R² have up to 12 carbon atoms, preferably 3 to8 carbon atoms, especially 3 to 6 carbon atoms. Suitable alkyl groupsfor R² include those listed above for R¹ as well as hexyl, heptyl,octyl, nonyl, decyl, undecyl, dodecyl, 1-, 2-, 3- or 4-methylpentyl,tert-butyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or2-ethylbutyl, ethylnethylpropyl, trimethylpropyl, methylhexyl,dimethylpentyl, ethylpentyl, ethylmethylbutyl, dimethylbutyl, and thelike.

[0194] Substituted alkyl groups are alkyl groups as described abovewhich are substituted in one or more positions by, for example,halogens, oxo, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄-alkoxy, and/orcyano. Halogens are preferred substituents, especially F and Cl.

[0195] Alkoxy groups means alkyl-O— groups in which the alkyl portion isin accordance with the previous discussion. Suitable alkoxy groups aremethoxy, ethoxy, propoxy and butoxy, pentoxy, hexoxy, heptoxy, octoxyand trifluoromethoxy. Preferred alkoxy groups are methoxy and ethoxy.Similarly, alkoxycarbonyl means alkyl —O—CO— in which the alkyl portionis in accordance with the previous discussion. Examples includemethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, andtert-butoxycarbonyl.

[0196] Alkenyl refers to straight-chain or branched-chain aliphaticradicals containing 2 to 12 carbon atoms in which one or more —CH₂—CH₂—structures are each replaced by —CH═CH—. Suitable alkenyl groups areethenyl, 1-propenyl, 2-methylethenyl, 1-butene, 2-butene, 1-pentenyl,and 2-pentenyl.

[0197] Alkynyl refers to straight-chain or branched-chain aliphaticradicals containing 2 to 12 carbon atoms in which one or more —CH₂—CH₂—structures are each replaced by —C≡C—. Suitable alkynyl groups areethynyl, propynyl, 1-butynyl, and 2-butynyl.

[0198] Cycloalkyl means a monocyclic, bicyclic or tricyclic nonaromaticsaturated hydrocarbon radical. Cycloalkyl radicals for R¹ have 3 to 6carbon atoms, preferably 3 to 5 carbon atoms, especially 3 carbon atoms.Suitable cycloalkyl groups for R¹ include cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl. Cycloalkyl radicals for R² have 3 to 12carbon atoms, preferably 3 to 10 carbon atoms, especially 4 to 8 carbonatoms. Suitable cycloalkyl groups for R² include those listed above forR¹ as well as cycloheptyl, cyclooctyl, cyclononyl, norbornyl, 1-decalin,adamant-1-yl, and adamant-2-yl. Other suitable cycloalkyl groups for R²include spiro[2,4]heptyl, spiro[2.5]octyl, bicyclo[5.1.0]octyl,bicyclo[2.2.0]hexyl, spiro[3.3]heptyl, and bicyclo[4.2.0]octyl.

[0199] The cycloalkyl group can be substituted. For example, it can besubstituted by halogens, C₁₋₄-alkyls, C₁₋₄-halogenated alkyls,C₁₋₄-alkoxy and/or cyano.

[0200] Cycloalkylalkyl refers to cycloalkyl-alkyl radicals in which thecycloalkyl and alkyl portions are in accordance with previousdiscussions. Suitable examples include cyclopropylmethyl andcyclopentylmethyl.

[0201] Alkyl ethers refer to C₃ to C₁₂ alkoxyalkyl radicals. Suitablealkyl ether groups include methoxyethyl, ethoxyethyl, and methoxypropyl.

[0202] Aryl, as a group or substituent per se or as part of a group orsubstituent, refers to an aromatic carbocyclic radical containing 6 to14 carbon atoms, preferably 6 to 12 carbon atoms, especially 6 to 10carbon atoms. Suitable aryl groups include phenyl, naphthyl andbiphenyl. Substituted aryl groups include the above-described arylgroups which are substituted one or more times by, for example, byhalogen, C₁₋₄-alkyl, C₁₋₄-halogenated alkyl, hydroxy, C₁₋₄-alkoxy,C₁₋₄-halogenated alkoxy, nitro, methylenedioxy, ethylenedioxy, amino,C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl,C₁₋₄-hydroxyalkoxy, carboxy, cyano, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl and phenoxy.

[0203] Arylalkyl refers to an aryl-alkyl-radical in which the aryl andalkyl portions are in accordance with the previous descriptions.Preferably, the aryl portion has 6 to 10 carbon atoms and the alkylportion, which is straight-chained or branched, has 1 to 6 carbon atoms,preferably 1 to 3 carbon atoms. The aryl portion can be substituted bythe substituents described above for aryl groups and the alkyl portioncan be substituted by oxo, halogens, cyano or combinations thereof.Suitable examples include benzyl, 1-phenethyl, 2-phenethyl, phenpropyl,fluorobenzyl, chlorobenzyl, methoxybenzyl, methylbenzyl and cyanobenzyl.

[0204] Heteroaryl refers to an aromatic heterocyclic group having one ortwo rings and a total number of 5 to 10 ring atoms wherein at least oneof the ring atoms is a heteroatom. Preferably, the heteroaryl groupcontains 1 to 3, especially 1 or 2, hetero-ring atoms which are selectedfrom N, O and S. Suitable heteroaryl groups include furyl, thienyl,pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl,oxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxatriazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, benzofuranyl,isobenzofuranyl, thionaphthenyl, isothionaphthenyl, indolyl, isoindolyl,indazolyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl,benzisothiazolyl, purinyl, benzopyranyl, quinolinyl, isoquinolinyl,cinnolinyl, quinazolinyl, naphthyridinyl, and benzoxazinyl, e.g.,2-thienyl, 3-thienyl, 2-, 3- or 4-pyridyl, 2-, 3-, 4-, 5-, 6-, 7- or8-quinolinyl, and 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl.

[0205] Substituted heteroaryl refers to the heteroaryl groups describedabove which are substitued in one or more places by, for example,halogen, hydroxyl, aryl, alkyl, alkoxy, carboxy, methylene, cyano,trifluoromethyl, nitro, oxo, amino, alkylamino, and dialkylamino.

[0206] Heteroarylalkyl refers to a heteroaryl-alkyl-group wherein theheteroaryl and alkyl portions are in accordance with the previousdiscussions. Suitable examples are pyridylmethyl, thienylmethyl,pyrimidinylmethyl, pyrazinylmethyl, and isoquinolinylmethyl.

[0207] Heterocycles are non-aromatic cyclic groups containing at leastone hetero-ring atom, preferably selected from N, S and O, for example,3-tetrahydrofuranyl, piperidinyl, imidazolinyl, imidazolidinyl,pyrrolinyl, pyrrolidinyl, morpholinyl, piperazinyl, and indolinyl.

[0208] Heterocycle-alkyl refers to a heterocycle-alkyl-group wherein theheterocyclic and alkyl portions are in accordance with the previousdiscussions. Suitable examples are piperidinyl-ethyl andpyrrolinyl-methyl.

[0209] Carbocycles are non-aromatic monocyclic or bicyclic structurescontaining 5 to 14 carbon atoms, preferably 6 to 10 carbon atoms.Suitable examples are cyclopentenyl, cyclohexenyl, cyclohexadienyl,tetrahydronaphthenyl and indan-2-yl.

[0210] Acyl refers to alkanoyl radicals having 1 to 6 carbon atoms inwhich the alkyl portion can be substituted by halogen, alkyl, aryland/or alkoxy, or aroyl radicals having 7 to 15 carbon atoms in whichthe aryl portion can be substituted by, for example, halogen, alkyland/or alkoxy. Suitable acyl groups include formyl, acetyl, propionyl,butanoyl and benzoyl.

[0211] Substituted radicals preferably have 1 to 3 substituents,especially 1 to 2 substituents.

[0212] R¹ is preferably H, alkyl such as methyl, ethyl and isopropyl,substituted alkyl, such as HOCH₂CH₂—, cycloalkyl such as cyclopropyl,cyclobutyl, and cyclopentyl, cycloalkylalkyl such as cyclopropylmethyl.In particular, R¹ is preferably methyl, ethyl or cycloalkyl such ascyclopropyl, cyclobutyl, or cyclopentyl, especially methyl, ethyl andcyclopropyl.

[0213] R² is preferably cycloalkyl, aryl, heteroaryl, carbocycle orhetero cycle. In particular, R² is preferably cycloalkyl such ascyclopentyl, cyclohexyl, cycloheptyl and norbornyl, aryl which isunsubstituted or substituted one or more times by, e.g., halogen,methoxy, nitro, cyano, amino or combinations thereof, heteroaryl such aspyridinyl, pyrimidinyl, thienyl, and furanyl which is unsubstituted orsubstituted by, for example, methoxy and/or methylthio, carbocycle suchas substituted or unsubstituted 2-indanyl, or heterocycle such assubstituted or unsubstituted piperidinyl, pyrrolydinyl, andtetrahydrofuranyl.

[0214] In addition, preferred PDE4 inhibitors, in accordance with theinvention, are compounds described by subformulas Ia-II, whichcorrespond to formula I, but exhibit the following preferred groups:

[0215] Ia R¹ is alkyl having 1 to 5 C atoms which is unsubstituted orsubstituted by hydroxy, cycloalkylalkyl having 4 to 6 carbon atoms, oris cycloalkyl having 3-5 C atoms; and

[0216] R² is alkyl having 3 to 8 C atoms, alkyl ether having 3 to 8carbon atoms, cycloalkyl having 3 to 9 carbon atoms, cycloalkylalkylhaving 4 to 10 carbon atoms, aryl having 6 to 10 carbon atoms,heterocycle having 5 to 10 ring atoms, heterocycle having 5 to 10 ringatoms, heterocycle-alkyl having 5 to 10 ring atoms, carbocycle having 5to 12 carbon atoms, or heteroaryl, heteroarylalkyl or arylalkyl having 7to 12 C atoms, wherein the heteroaryl or aryl portion is unsubstitutedor substituted one more times by halogens, alkyl, CN, alkoxy, nitro,alkoxy, or the combinations thereof and the alkyl portion isunsubstituted or substituted by halogen thereof.

[0217] Ib R¹ is cyclopropyl; and

[0218] R² is benzyl, phenethyl, or phenpropyl, which in each case issubstituted 1 to 3 times by halogens, C₁₋₄ alkyl, C₁₋₄ alkoxy orcombinations thereof.

[0219] Ic R¹ is cyclopropyl; and

[0220] R² is alkyl having 3 to 8 C atoms or arylalkyl having 7 to 12 Catoms wherein the aryl portion is substituted one more time by halogens,alkyl, CN, alkoxy, nitro, or combinations thereof.

[0221] Id R¹ is cyclopropyl; and

[0222] R² is benzyl, 2-methylbenzyl, 3-methylbenzyl, 2-chlorobenzyl,3-chlorobenzyl, 4-chlorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl,4-fluorobenzyl, 3-methoxybenzyl, 4-cyanobenzyl, 2-triflouromethylbenzyl,3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl,3,5-di(trifluoromethyl)benzyl, 2,4-difluorobenzyl, 3,4-difluorobenzyl,3,5-difluorobenzyl, 2,6-difluorobenzyl, 2,3-difluorobenzyl,2-chloro-4-fluorobenzyl, 3-chloro-4-chlorobenzyl, 2-chloro-phenethyl,2-fluoro-phenethyl, 2-methyl-phenethyl, 3-chlorophenethyl,3-methylphenethyl, 3-methylphenethyl, 3-methoxyphenethyl,4-chlorophenethyl, 4-methylphenethyl, 4-methoxyphenethyl,2-methoxy-phenpropyl, 4-chloro-phenpropyl, 4-methoxy-phenpropyl.

[0223] Ie R¹ is cyclopropyl; and

[0224] R² is heteroarylalkyl which is unsubstituted or substituted 1 to3 halogen, C₁₋₄-alkyl, C₁₋₄-alkoxy or combinations thereof.

[0225] If R¹ is cyclopropyl; and

[0226] R² is 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl,2-thienylmethyl, 3-thienylmethyl, 2-furylmethyl or 3-furylmethyl.

[0227] Ig R¹ is methyl, ethyl, or cyclopropyl; and

[0228] R² is cycloalkyl.

[0229] Ih R¹ is methyl, ethyl, or cyclopropyl; and

[0230] R² is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl ornorbornyl.

[0231] Ii R¹ is methyl, ethyl, or cyclopropyl; and

[0232] R² is aryl (e.g., phenyl) or substituted aryl (e.g., substitutedphenyl).

[0233] Ij R¹ is methyl, ethyl, or cyclopropyl; and

[0234] R² is carbocycle (e.g., 2-indanyl).

[0235] Ik R¹ is methyl, ethyl, or cyclopropyl; and

[0236] R² is heterocycle (e.g., piperidinyl).

[0237] Il R¹ is methyl, ethyl, or cyclopropyl; and

[0238] R² is heteroaryl or substituted heteroaryl (e.g., substituted orunsubstituted pyrimdinyl, pyridyl, thienyl, and furanyl.

[0239] Preferred aspects include pharmaceutical compositions comprisinga compound of this invention and a pharmaceutically acceptable carrierand, optionally, another active agent as discussed below; a method ofinhibiting a PDE4 enzyme, especially an isoenzyme, e.g., as determinedby a conventional assay or one described herein, either in vitro or invivo (in an animal, e.g., in an animal model, or in a mammal or in ahuman); a method of treating neurological syndrome, e.g., loss ofmemory, especially long-term memory, cognitive impairment or decline,memory impairment, etc.; a method of treating a disease state modulatedby PDE4 activity, in a mammal, e.g., a human, e.g., those mentionedherein.

[0240] The compounds of the present invention may be preparedconventionally. Some of the processes which can be used are describedbelow. All starting materials are known or can be conventionallyprepared from known starting materials.

[0241] 2-Substituted hypoxanthines are produced by standard methods inthe art, such as by neat reaction between 4-amino-5-imidazolecarboxamideand 2,2,2-trifluoroacetamide (E. Richter et al, J. Am. Chem. Soc. 1960,82, 3144-3146; or A. Giner-Sorala, et al, J. Am. Chem. Soc. 1958, 80,5744-5752; or A. Parkin, et al, J. Heterocycl. Chem. 1982, 19, 33-40).6-Halo-2-trifluoromethylpurine may be prepared by methods common in theart (see J.-J. Bourguignon, et al., J. Med. Chem. 1997, 40, 1768-1770;and H. Bader, et al., U.S. Pat. No. 4,405,781, 1983) such as by reactionwith a halogenating reagent such as with SOCl₂, or POCl₃, or PCl₅. Thesereactions can be run neat or with a polar aprotic solvent such asdichloromethane, dichloroethane, or N,N-dimethylformamide. Reaction of a6-halopurine (e.g. 6-chloro-2-trifluoromethylpurine) with either analkyl halide, cycloalkyl halide, cycloalkylalkyl halide, heteroarylhalide or arylalkyl halide in a polar aprotic solvent such asN,N-dimethylforamide, dimethylsulfoxide, or dimethoxyethane in thepresence of a base (e.g. K₂CO₃, Na₂CO₃, NaH) provides a mixture of 9-and 7-substituted 6-halopurines.

[0242] The use of a phase transfer catalyst, for example, 18-crown-6 ortetrabutylammonium chloride, with increased reaction temperature, e.g.,60° C. to 150° C., can be used to enhance reaction rates or reactionyields. Alternatively, reaction of a 6-halopurine under Mitsunobuconditions with an alkyl alcohol, cycloalkyl alcohol, arylalkyl alcohol,heteroaryl alcohol, or cycloalkylalkyl alcohol provides a mixture of 9-and 7-substituted 6-halopurines. The 9- and 7-isomers produced by thereactions described above are readily separated by chromatography. Such9-substituted-6-halopurines undergo reaction with amines (e.g. anmmonia,alkylamines, cycloalkylamines, or cycloalkylalkylamines) to provideadenine derivatives of formulas I-III.

[0243] Alternatively, 6-halo-2-substituted purines readily undergoreaction with amines (e.g. ammonia, alkylamines, cycloalkylamines, orcycloalkylalkylamines) in the presence of polar protic solvents (e.g.methanol, ethanol, propanol etc.) to yield 6-N-substituted adenineanalogs. Reaction with either an alkyl halide, cycloalkyl halide,cycloalkylalkyl halide, heteroaryl halide or arylalkyl halide in a polaraprotic solvent such as N,N-dimethylformamide, dimethylsulfoxide, ordimethoxyethane, and in the presence of a base (e.g. K₂CO₃, Na₂CO₃, NaH)provides adenine derivatives of formulas I-III. The use of a phasetransfer catalyst, for example, 18-crown-6 or tetrabutylammoniumchloride, with

[0244] increased reaction temperature, e.g., 60° C. to 150° C., can beused to enhance reaction rates or reaction yields. Alternatively,reaction of 6-N-substituted adenines under Mitsunobu conditions with analkyl alcohol, cycloalkyl alcohol, arylalkyl alcohol, heteroarylalcohol, or cycloalkylalkyl alcohol provides 9-substituted6-N-substituted adenines of formulas I-III.

[0245] 6-N-Substituted-9-aryl- and 9-heteroaryl-adenines may besynthesized by methods common to the art, such as by reaction of a4,6-dichloro-5-aminopyrimidine with an appropriately substituted anilineor heteroarylamine as described by J. L. Kelley et. al., J. Med. Chem.,1997, 40, 3207 to produce 4-arylamino or4-heteroarylamino-6-chloropyrimidines. Cyclization by treating withtriethylorthoformate in the presence of an acid catalyst (e.g.ethylsulfonic acid) provides 6-choro-9-aryl- or 9-heteroaryl-purines,which can be derivatized at the 6-N-position as described above toprovide adenine derivatives of formulas I-III.

[0246] Alternatively, 6-N-substituted adenines may undergo a couplingreaction with arylboronic acids or heteroarylboronic acids in thepresence of a base (e.g. triethylamine, pyridine, N—

[0247] methylmorpholine), a copper catalyst (e.g., Cu(OAc)₂), and apolar aprotic solvent (e.g. dichloromethane, 1,4-dioxane, THF, DMF,CH₃CN) in a modoified manner as described previously for the N-arylationof imidazole and pyrazole (see, P. Y. S. Lam et. al.

[0248] Tetrahedron Lett. 1998, 39, 2941-2944) to generate 9-aryl- or9-heteroaryl-adenines of formulas I-III. Thus, preferably, the use oftriethylamine, rather than pyridine, as a base, and warming to 50-60° C.in CH₃CN, rather than stirring at room temperature in CH₂Cl₂, providesthe novel compounds.

[0249] Alternatively, certain halogenated aryl and heteroaryl substratescan undergo aromatic nucleophilic substitution reaction with6-(substituted)amino-2-trifluoromethylpurine in a polar aprotic solvent(e.g., DMF or DMSO) using a base (e.g., cesium carbonate) to providetarget 9-aryl or 9-heteroarylpurines.

[0250] Many of these synthetic procedures are described more fully inthe examples below.

[0251] One of ordinary skill in the art will recognize that some of thecompounds of Formulas I-III can exist in different geometrical isomericforms. In addition, some of the compounds of the present inventionpossess one or more asymmetric carbon atoms and are thus capable ofexisting in the form of optical isomers, as well as in the form ofracemic or nonracemic mixtures thereof, and in the form of diastereomersand diastereomeric mixtures inter alia. All of these compounds,including cis isomers, trans isomers, diastereomic mixtures, racemates,nonracemic mixtures of enantiomers, and substantially pure and pureenantiomers, are within the scope of the present invention.

[0252] Substantially pure enantiomers contain no more than 5% w/w of thecorresponding opposite enantiomer, preferably no more than 2%, mostpreferably no more than 1%.

[0253] The optical isomers can be obtained by resolution of the racemicmixtures according to conventional processes, for example, by theformation of diastereoisomeric salts using an optically active acid orbase or formation of covalent diastereomers. Examples of appropriateacids are tartaric, diacetyltartaric, dibenzoyltartaric,ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomerscan be separated into their individual diastereomers on the basis oftheir physical and/or chemical differences by methods known to thoseskilled in the art, for example, by chromatography or fractionalcrystallization. The optically active bases or acids are then liberatedfrom the separated diastereomeric salts. A different process forseparation of optical isomers involves the use of chiral chromatography(e.g., chiral HPLC columns), with or without conventional derivation,optimally chosen to maximize the separation of the enantiomers. Suitablechiral HPLC columns are manufactured by Diacel, e.g., Chiracel OD andChiracel OJ among many others, all routinely selectable. Enzymaticseparations, with or without derivitization, are also useful. Theoptically active compounds of Formulae I-III can likewise be obtained bychiral syntheses utilizing optically active starting materials.

[0254] The present invention also relates to useful forms of thecompounds as disclosed herein, such as pharmaceutically acceptable saltsand prodrugs of all the compounds of the present invention.Pharmaceutically acceptable salts include those obtained by reacting themain compound, functioning as a base, with an inorganic or organic acidto form a salt, for example, salts of hydrochloric acid, sulfuric acid,phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalicacid, maleic acid, succinic acid and citric acid. Pharmaceuticallyacceptable salts also include those in which the main compound functionsas an acid and is reacted with an appropriate base to form, e.g.,sodium, potassium, calcium, mangnesium, ammonium, and choline salts.Those skilled in the art will further recognize that acid addition saltsof the claimed compounds may be prepared by reaction of the compoundswith the appropriate inorganic or organic acid via any of a number ofknown methods. Alternatively, alkali and alkaline earth metal salts areprepared by reacting the compounds of the invention with the appropriatebase via a variety of known methods.

[0255] The following are further examples of acid salts that can beobtained by reaction with inorganic or organic acids: acetates,adipates, alginates, citrates, aspartates, benzoates, benzenesulfonates,bisulfates, butyrates, camphorates, digluconates,cyclopentanepropionates, dodecylsulfates, ethanesulfonates,glucoheptanoates, glycerophosphates, hemisulfates, heptanoates,hexanoates, fumarates, hydrobromides, hydroiodides,2-hydroxy-ethanesulfonates, lactates, maleates, methanesulfonates,nicotinates, 2-naphthalenesulfonates, oxalates, palmoates, pectinates,persulfates, 3-phenylpropionates, picrates, pivalates, propionates,succinates, tartrates, thiocyanates, tosylates, mesylates andundecanoates.

[0256] Preferably, the salts formed are pharmaceutically acceptable foradministration to mammals. However, pharmaceutically unacceptable saltsof the compounds are suitable as intermediates, for example, forisolating the compound as a salt and then converting the salt back tothe free base compound by treatment with an alkaline reagent. The freebase can then, if desired, be converted to a pharmaceutically acceptableacid addition salt.

[0257] The compounds of the invention can be administered alone or as anactive ingredient of a formulation. Thus, the present invention alsoincludes pharmaceutical compositions of compounds of Formula Icontaining, for example, one or more pharmaceutically acceptablecarriers.

[0258] Numerous standard references are available that describeprocedures for preparing various formulations suitable for administeringthe compounds according to the invention. Examples of potentialformulations and preparations are contained, for example, in theHandbook of Pharmaceutical Excipients, American PharmaceuticalAssociation (current edition); Pharmaceutical Dosage Forms: Tablets(Lieberman, Lachman and Schwartz, editors) current edition, published byMarcel Dekker, Inc., as well as Remington's Pharmaceutical Sciences(Arthur Osol, editor), 1553-1593 (current edition).

[0259] In view of their high degree of PDE4 inhibition, the compounds ofthe present invention can be administered to anyone requiring ordesiring PDE4 inhibition, and/or enhancement of cognition.Administration may be accomplished according to patient needs, forexample, orally, nasally, parenterally (subcutaneously, intraveneously,intramuscularly, intrasternally and by infusion), by inhalation,rectally, vaginally, topically, locally, transdermally, and by ocularadministration.

[0260] Various solid oral dosage forms can be used for administeringcompounds of the invention including such solid forms as tablets,gelcaps, capsules, caplets, granules, lozenges and bulk powders. Thecompounds of the present invention can be administered alone or combinedwith various pharmaceutically acceptable carriers, diluents (such assucrose, mannitol, lactose, starches) and excipients known in the art,including but not limited to suspending agents, solubilizers, bufferingagents, binders, disintegrants, preservatives, colorants, flavorants,lubricants and the like. Time release capsules, tablets and gels arealso advantageous in administering the compounds of the presentinvention.

[0261] Various liquid oral dosage forms can also be used foradministering compounds of the invention, including aqueous andnon-aqueous solutions, emulsions, suspensions, syrups, and elixirs. Suchdosage forms can also contain suitable inert diluents known in the artsuch as water and suitable excipients known in the art such aspreservatives, wetting agents, sweeteners, flavorants, as well as agentsfor emulsifying and/or suspending the compounds of the invention. Thecompounds of the present invention may be injected, for example,intravenously, in the form of an isotonic sterile solution. Otherpreparations are also possible.

[0262] Suppositories for rectal administration of the compounds of thepresent invention can be prepared by mixing the compound with a suitableexcipient such as cocoa butter, salicylates and polyethylene glycols.Formulations for vaginal administration can be in the form of a pessary,tampon, cream, gel, paste, foam, or spray formula containing, inaddition to the active ingredient, such suitable carriers as are knownin the art.

[0263] For topical administration the pharmaceutical composition can bein the form of creams, ointments, liniments, lotions, emulsions,suspensions, gels, solutions, pastes, powders, sprays, and dropssuitable for administration to the skin, eye, ear or nose. Topicaladministration may also involve transdermal administration via meanssuch as transdermal patches.

[0264] Aerosol formulations suitable for administering via inhalationalso can be made. For example, for treatment of disorders of therespiratory tract, the compounds according to the invention can beadministered by inhalation in the form of a powder (e.g., micronized) orin the form of atomized solutions or suspensions. The aerosolformulation can be placed into a pressurized acceptable propellant.

[0265] The compounds can be administered as the sole active agent or incombination with other pharmaceutical agents such as other agents usedin the treatment of cognitive impairment and/or in the treatment ofpsychosis, e.g., other PDE4 inhibitors, calcium channel blockers,chloinergic drugs, adenosine receptor modulators, amphakines NMDA-Rmodulators, mGluR modulators, and cholinesterase inhibitors (e.g.,donepezil, rivastigimine, and glanthanamine). In such combinations, eachactive ingredient can be administered either in accordance with theirusual dosage range or a dose below its usual dosage range.

[0266] The present invention further includes methods of treatment thatinvolve inhibition of PDE4 enzymes. Thus, the present invention includesmethods of selective inhibition of PDE4 enzymes in animals, e.g.,mammals, especially humans, wherein such inhibition has a therapeuticeffect, such as where such inhibition may relieve conditions involvingneurological syndromes, such as the loss of memory, especially long-termmemory. Such methods comprise administering to an animal in needthereof, especially a mammal, most especially a human, an inhibitoryamount of a compound, alone or as part of a formulation, as disclosedherein.

[0267] The condition of memory impairment is manifested by impairment ofthe ability to learn new information and/or the inability to recallpreviously learned information. Memory impairment is a primary symptomof dementia and can also be a symptom associated with such diseases asAlzheimer's disease, schizophrenia, Parkinson's disease, Huntington'sdisease, Pick's disease, Creutzfeld-Jakob disease, HIV, cardiovasculardisease, and head trauma as well as age-related cognitive decline.

[0268] Dementias are diseases that include memory loss and additionalintellectual impairment separate from memory. The present inventionincludes methods for treating patients suffering from memory impairmentin all forms of dementia. Dementias are classified according to theircause and include: neurodegenerative dementias (e.g., Alzheimer's,Parkinson's disease, Huntington's disease, Pick's disease), vascular(e.g., infarcts, hemorrhage, cardiac disorders), mixed vascular andAlzheimer's, bacterial meningitis, Creutzfeld-Jacob Disease, multiplesclerosis, traumatic (e.g., subdural hematoma or traumatic braininjury), infectious (e.g., HIV), genetic (down syndrome), toxic (e.g.,heavy metals, alcohol, some medications), metabolic (e.g., vitamin B12or folate deficiency), CNS hypoxia, Cushing's disease, psychiatric(e.g., depression and schizophrenia), and hydrocephalus.

[0269] The present invention includes methods for dealing with memoryloss separate from dementia, including mild cognitive impairment (MCI)and age-related cognitive decline. The present invention includesmethods of treatment for memory impairment as a result of disease. Inanother application, the invention includes methods for dealing withmemory loss resulting from the use of general anesthetics, chemotherapy,radiation treatment, post-surgical trauma, and therapeutic intervention.

[0270] The compounds may be used to treat psychiatric conditionsincluding schizophrenia, bipolar or manic depression, major depression,and drug addiction and morphine dependence. These compounds may enhancewakefulness. PDE4 inhibitors can be used to raise cAMP levels andprevent neurons from undergoing apoptosis. PDE4 inhibitors are alsoknown to be anti-inflammatory. The combination of anti-apoptotic andanti-inflammatory properties make these compounds useful to treatneurodegeneration resulting from any disease or injury, includingstroke, spinal cord injury, neurogenesis, Alzheimer's disease, multiplesclerosis, amylolaterosclerosis (ALS), and multiple systems atrophy(MSA).

[0271] Thus, in accordance with a preferred embodiment, the presentinvention includes methods of treating patients suffering from memoryimpairment due to, for example, Alzheimer's disease, schizophrenia,Parkinson's disease, Huntington's disease, Pick's disease,Creutzfeld-Jakob disease, depression, aging, head trauma, stroke, CNShypoxia, cerebral senility, multiinfarct dementia and other neurologicalconditions including acute neuronal diseases, as well as HIV andcardiovascular diseases, comprising administering an effective amount ofa compound according to Formula (I) or (I′) or pharmaceuticallyacceptable salts thereof.

[0272] The compounds of the present invention can also be used in amethod of treating patients suffering from disease states characterizedby decreased NMDA function, such as schizophrenia. The compounds canalso be used to treat psychosis characterized by elevated levels of PDE4, for example, various forms of depression, such as manic depression,major depression, and depression associated with psychiatric andneurological disorders.

[0273] As mentioned, the compounds of the invention also exhibitanti-inflammatory activity. As a result, the inventive compounds areuseful in the treatment of a variety of allergic and inflammatorydiseases, particularly disease states characterized by decreased cyclicAMP levels and/or elevated phosphodiesterase 4 levels. Thus, inaccordance with a farther embodiment of the invention, there is provideda method of treating allergic and inflammatory disease states,comprising administering an effective amount of a compound according toFormulae (I) or (I′) or a pharmaceutically acceptable salt thereof. Suchdisease states include: asthma, chronic bronchitis, chronic obstructivepulmonary disease (COPD), atopic dermatitis, urticaria, allergicrhinitis, allergic conjunctivitis, vernal conjunctivitis, esoniophilicgranuloma, psoriasis, inflammatory arthritis, rheumatoid arthritis,septic shock, ulcerative colitis, Crohn's disease, reperfusion injury ofthe myocardium and brain, chronic glomerulonephritis, endotoxic shock,adult respiratory distress syndrome, cystic fibrosis, arterialrestenosis, artherosclerosis, keratosis, rheumatoid spondylitis,osteoarthritis, pyresis, diabetes mellitus, pneumoconiosis, chronicobstructive airways disease, chronic obstructive pulmonary disease,toxic and allergic contact eczema, atopic eczema, seborrheic eczema,lichen simplex, sunburn, pruritis in the anogenital area, alopeciaareata, hypertrophic scars, discoid lupus erythematosus, systemic lupuserythematosus, follicular and wide-area pyodermias, endogenous andexogenous acne, acne rosacea, Beghet's disease, anaphylactoid purpuranephritis, inflammatory bowel disease, leukemia, multiple sclerosis,gastrointestinal diseases, autoimmune diseases and the like.

[0274] PDE4 inhibitors for treating asthma, chronic bronchitis,psoriasis, allergic rhinitis, and other inflammatory diseases, and forinhibiting tumor necrosis factor are known within the art. See, e.g., WO98/58901, JP11-18957, JP 10-072415, WO 93/25517, WO 94/14742, U.S. Pat.No. 5,814,651, and U.S. Pat. No. 5,935,9778. These references alsodescribe assays for determining PDE4 inhibition activity, and methodsfor synthesizing such compounds. The entire disclosures of thesedocuments are hereby incorporated by reference.

[0275] PDE4 inhibitors may be used to prevent or ameliorateosteoporosis, as an antibiotic, for treatment of cardiovascular diseaseby mobilizing cholesterol from atherosclerotic lesions, to treatrheumatoid arthritis (RA), for long-term inhibition of mesenchymal-cellproliferation after transplantation, for treatment of urinaryobstruction secondary to benign prostatic hyperplasia, for suppressionof chemotaxis and reduction of invasion of colon cancer cells, fortreatment of B cell chronic lymphocytic leukemia (B-CLL), for inhibitionof uterine contractions, to attenuate pulmonary vascularischemia-reperfusion injury (IRI), for corneal hydration, for inhibitionof IL-2R expression and thereby abolishing HIV-1 DNA nuclear import intomemory T cells, for augmentation of glucose-induced insulin secretion,in both the prevention and treatment of colitis, and to inhibit mastcell degranulation.

[0276] The compounds of the present invention can be administered as thesole active agent or in combination with other pharmaceutical agentssuch as other agents used in the treatment of cognitive impairmentand/or in the treatment of psychosis, e.g., other PDE4 inhibitors,calcium channel blockers, chloinergic drugs, adenosine receptormodulators, amphakines NMDA-R modulators, mGluR modulators, andcholinesterase inhibitors (e.g., donepezil, rivastigimine, andglanthanamine). In such combinations, each active ingredient can beadministered either in accordance with their usual dosage range or adose below their usual dosage range.

[0277] The dosages of the compounds of the present invention depend upona variety of factors including the particular syndrome to be treated,the severity of the symptoms, the route of administration, the frequencyof the dosage interval, the particular compound utilized, the efficacy,toxicology profile, pharmacokinetic profile of the compound, and thepresence of any deleterious side-effects, among other considerations.

[0278] The compounds of the invention are typically administered atdosage levels and in a mammal customary for PDE4 inhibitors such asthose known compounds mentioned above. For example, the compounds can beadministered, in single or multiple doses, by oral administration at adosage level of, for example, 0.01-100 mg/kg/day, preferably 0.1-70mg/kg/day, especially 0.5-10 mg/kg/day. Unit dosage forms can contain,for example, 0.1-50 mg of active compound. For intravenousadministration, the compounds can be administered, in single or multipledosages, at a dosage level of, for example, 0.001-50 mg/kg/day,preferably 0.001-10 mg/kg/day, especially 0.01-1 mg/kg/day. Unit dosageforms can contain, for example, 0.1-10 mg of active compound.

[0279] In carrying out the procedures of the present invention it is ofcourse to be understood that reference to particular buffers, media,reagents, cells, culture conditions and the like are not intended to belimiting, but are to be read so as to include all related materials thatone of ordinary skill in the art would recognize as being of interest orvalue in the particular context in which that discussion is presented.For example, it is often possible to substitute one buffer system orculture medium for another and still achieve similar, if not identical,results. Those of skill in the art will have sufficient knowledge ofsuch systems and methodologies so as to be able, without undueexperimentation, to make such substitutions as will optimally servetheir purposes in using the methods and procedures disclosed herein.

[0280] The present invention will now be further described by way of thefollowing non-limiting examples. In applying the disclosure of theseexamples, it should be kept clearly in mind that other and differentembodiments of the methods disclosed according to the present inventionwill no doubt suggest themselves to those of skill in the relevant art.

[0281] In the foregoing and in the following examples, all temperaturesare set forth uncorrected in degrees Celsius; and, unless otherwiseindicated, all parts and percentages are by weight.

[0282] The entire disclosures of all applications, patents andpublications, cited above and below, are hereby incorporated byreference.

EXAMPLE 1

[0283] 1,9-Dihydro-2-trifluoromethyl-6H-purin-6-one (Kelly, J. L.; Linn,J. A.; Selway, J. W. T., J. Med. Chem., 1989, 32, 1757-1763.)

[0284] A 1 L round-bottom flask (three neck) containing 340 g oftrifluoroacetamide was heated in an oil bath at 110° C. After thetrifluoroacetamide melted, 50 g of 5-aminoimidazole-4-carboxamide-HClwas added. The mixture was warmed to reflux (bath temp 160 to 165° C.)for 4 hours, cooled to room temperature, and the rocky solid wastriturated with 1 L of ether. The ether was decanted off and theremaining solid was warmed until melted and 200 mL of ether wasintroduced by a dropping-funnel through a water-cooled condenser. Themixture was cooled to room temperature and an additional 200 mL of etherwas added with stirring. The solid was removed by filtration, trituratedwith 3×500 mL of ether, washed with 200 mL of H₂O, and filtered toprovide 89 g of crude product. The product was treated with 3 L of MeOHand 9 g of activated carbon, warmed to reflux for 20 minutes, filteredthrough a pad of celite, and concentrated to a volume of 2.5 L. Thematerial was warmed to dissolve all the precipitate that formed and thencooled slowly to room temperature. The crystalline material was isolatedby filtration and dried in vacuo to provide 41 g of the desiredhypoxanthine as a white solid. ¹H NMR (DMSO-d₆) δ 8.34 (s, 1H), 7.18(bs, 2H). MS (ES+), 205.0 (100%, M+H).

EXAMPLE 2

[0285] 6-Chloro-2-trifluoromethylpurine

[0286] A mixture of 15 g (73 mmol) of 2-trifluoromethylhypoxanthine and300 mL of CHCl₃ was warmed to reflux and treated with a solution of 26.7mL (366 mmol) SOCl₂ and 28.3 mL (366 mmol) DMF. The reaction wasmaintained at reflux for 1.5 h, cooled to room temperature, and pouredinto 1.2 L of ice-water. The organic layer was separated and washed with2×300 mL of H₂O. The pH of the combined aqueous phases was adjusted to 7with saturated NaHCO₃ and extracted with 3×1.2 L of ether. The combinedether and chloroform extracts were dried (MgSO₄) and concentrated todryness to give 7.4 g of crude product. ¹H NMR (DMSO-d₆) δ 14.45 (bs,1H), 8.95 (s, 1H). MS (ES+) 222.96 (100%, M+H).

EXAMPLE 3

[0287] 6-Chloro-9-(2-fluorobenzyl)-2-trifluoromethylpurine

[0288] A mixture of 5 g (22.5 mmol) of 6-chloro-2 trifluoromethylpurine,4.05 g (29.4 mmol) of anhydrous K₂CO₃, 56 mL of dry DMF, and 3.55 mL(29.4 mmol) of 2-fluorobenzyl bromide was stirred at room temperaturefor 16 h. The reaction mixture was poured into 50 mL of ice-water andthe pH of the solution was adjusted to 5 or 6 with acetic acid. Themixture was extracted with 3×300 mL of ether and the combined organicfractions were washed with 3×350 mL of H₂O, 300 mL of brine, dried(Na₂SO₄), and concentrated in vacuo to provide a yellow oil.Purification by chromatography over silica gel using a gradient elutiongoing from 20% EtOAc in hexanes to 50% EtOAc in hexanes provided 3.5 g(47% yield) of the desired 9-isomer (first to elute) and 1.97 g (27%yield) of the 7-isomer. ¹H NMR (CDCl₃) δ 8.33 (s, 1H), 7.50-7.47 (m,1H), 7.40-7.38 (m, 1H), 7.20-7.11 (m, 2H), 5.56 (s, 2H).

EXAMPLE 4

[0289] 6-Cyclopropylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine

[0290] A mixture of 100 mg (0.30 mmol) of6-chloro-9-(2-fluorobenzyl)-2-trifluoromethylpurine, 1 mL (14 mmol) ofaminocyclopropane, and 5 mL of EtOH were stirred at room temperature for16 hours. The reaction mixture was concentrated in vacuo and the residuewas dissolved in CH₂Cl₂, washed with 2×5 mL H₂O, 5 mL brine, dried(Na₂SO₄), and concentrated. Chromatography over silica gel using 33%EtOAc in hexanes as eluant provided 102 mg (97% yield) of the desiredproduct. M.P. 118.5-119.0° C.; ¹H NMR (CDCl₃) δ 7.892 (s, 1H), 7.50-7.39(m, 1H), 7.37-7.29 (m, 1H), 7.18-7.05 (m, 2H), 5.95 (bs, 1H), 5.44 (s,2H), 0.94-0.91 (m, 2H), 0.65-0.64 (m, 2H).

[0291] To obtain the methansulphonate salt (mesylate salt), 4 ml of 0.1NCH₃SO₃H in EtOAc was added to a solution of 145 mg (0.4 mmol)6-cyclopropylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine in EtOAc.Then, 1 ml of hexane was added to a warm solution and the resultantmixture was allowed to crystallize (within a refrigerator). The solidwas collected to give 148 mg of the mesylate salt. The salt wasrelatively insoluble in H₂O. M.p. 167.5-169.0 C; m.p. 114-118 C for freebase.

[0292] The following compounds were prepared in a similar fashion asdescribed above.

[0293] a. 6-Methylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine

[0294] b. 6-Ethylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine

[0295] c. 6-Amino-9-(2-fluorobenzyl)-2-trifluoromethylpurine

[0296] d.6-N-Cyclopropylmethylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine

[0297] e.6-[1-(2-Hydroxy)ethyl]amino-9-(2-fluorobenzyl)-2-trifluoromethylpurine

[0298] f. 6-Cyclopentylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine

[0299] g. 6-Cyclohexylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine

[0300] h. 6-Isopropylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine

EXAMPLE 5

[0301] 6-Cyclopropylamino-2-trifluoromethylpurine

[0302] A mixture of 12 g (54 mmol) of 6-chloro-2-trifluoromethylpurine,30 g (540 mmol) of cyclopropylamine and 250 mL of ethanol was stirred atroom temperature for 4.5 days leaving a white solid. The mixture wasconcentrated in vacuo to dryness, 215 mL of H₂O was added and themixture was stirred for 1 hour. The product was collected by filtrationand after drying (vacuum oven, 50° C., 5 hours) 8.1 g of product wasobtained, 62% yield. M.P. 260° C. (dec.); ¹H NMR (CD₃OD) δ 8.18 (s, 1H),3.30 (bs, 1H), 0.904 (m, 2H), 0.67 (m, 2H).

[0303] The following compounds are prepared in a similar manner:

[0304] a. 6-Methylamino-2-trifluuoromethylpurine

[0305] b. 6-Cyclopentylamino-2-trifluoromethylpurine

EXAMPLE 6

[0306] 6-Cyclopropylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine

[0307] To a nitrogen flushed tube with stir bar was added 25 mg (0.13mmol) of 2-fluorobenzyl bromide, 0.7 mL of anhydrous DMF, 18 mg (0.13mmol) of K₂CO₃ and 0.5 mL (0.10 mmol) of 0.2M6-cyclopropylamino-2-trifluoromethyladenine in anhydrous DMF. Thereaction was stirred at room temperature for 18 hours, quenched with 2mL of ice water and the pH was adjusted to between 5 and 6 with aceticacid. The aqueous mixture was extracted with 10 mL of ether and theether fraction was washed with 3 mL of H₂O, 3 mL of brine, dried (MgSO₄)and concentrated to dryness in vacuo. M.P. 118.5-119.0° C.; ¹H NMR(CDCl₃) δ 7.892 (s, 1H), 7.50-7.39 (m, 1H), 7.37-7.29 (m, 1H), 7.18-7.05(m, 2H), 5.95 (bs, 1H), 5.44 (s, 2H), 0.94-0.91 (m, 2H), 0.65-0.64 (m,2H).

[0308] The following compounds were prepared in a similar manner.

[0309] a. 6-Cyclopropylamino-9-(3-methoxybenzyl)-2-trifluoromethylpurine

[0310] b. 6-Cyclopropylamino-9-(3-chlorobenzyl)-2-trifluoromethylpurine

[0311] c. 6-Cyclopropylamino-9-(3-nitrobenzyl)-2-trifluoromethylpurine

[0312] d. 6-Cyclopropylamino-9-(4-cyanobenzyl)-2-trifluoromethylpurine

[0313] e.6-Cyclopropylamino-9-(4-trifluoromethylbenzyl)-2-trifluoromethylpurine

[0314] f.6-Cyclopropylamino-9-(3,4-dichlorobenzyl)-2-trifluoromethylpurine

[0315] g. 6-Cyclopropylamino-9-(4-chloro benzyl)-2-trifluoromethylpurine

[0316] h.6-Cyclopropylamino-9-(3,4-difluorobenzyl)-2-trifluoromethylpurine

[0317] i. 6-Cyclopropylamino-9-(3-pyridylmethyl)-2-trifluoromethylpurine

[0318] j.6-Cyclopropylamino-9-[a-(2-chloroacetophenone)]-2-trifluoromethylpurine

[0319] k.6-Cyclopropylamino-9-[a-(4-methoxyacetophenone)]-2-trifluoromethylpurine

[0320] l.6-Cyclopropylamino-9-(3,5-difluorobenzyl)-2-trifluoromethylpurine

[0321] m. 6-Cyclopropylamino-9-ethyl-2-trifluoromethylpurine

[0322] n.6-Cyclopropylamino-9-[a-(4-methylacetophenone)]-2-trifluoromethylpurine

[0323] o.6-Cyclopropylamino-9-(3-trifluoromethylbenzyl)-2-trifluoromethylpurine

[0324] p.6-Cyclopropylamino-9-(3,5-bistrifluoromethylbenzyl)]-2-trifluoromethylpurine

[0325] q.6-Cyclopropylamino-9-(4-methylsulfonylbenzyl)]-2-trifluoromethylpurine

[0326] r. 6-Cyclopropylamino-9-(4-nitrobenzyl)-2-trifluoromethylpurine

[0327] s.6-Cyclopropylamino-9-(4-tert-butylbenzyl)-2-trifluoromethylpurine

[0328] t. 6-Cyclopropylamino-9-(1-pentan-3-one)-2-trifluoromethylpurine

[0329] u.6-Cyclopropylamino-9-[α-(2-methoxyacetophenone)]-2-trifluoromethylpurine

[0330] v.6-Cyclopropylamino-9-[α-(4-cyanoacetophenone)]-2-trifluoromethylpurine

[0331] w.6-Cyclopropylamino-9-[α-(3-chloroacetophenone)]-2-trifluoromethylpurine

[0332] x.6-Cyclopropylamino-9-[α-(3-methoxyacetophenone)]-2-trifluoromethylpurine

[0333] y.6-Cyclopropylamino-9-[α-(4-chloroacetophenone)]-2-trifluoromethylpurine

[0334] z.6-Cyclopropylamino-9-[α-(3,4-dichloroacetophenone)-2-trifluoromethylpurine

[0335] aa.6-Cyclopropylamino-9-(4-pyridylmethyl)-2-trifluoromethylpurine

[0336] bb.6-Cyclopropylamino-9-(2-pyridylmethyl)-2-trifluoromethylpurine

[0337] cc. 6-Cyclopropylamino-9-(4-ethylbenzyl-2-trifluoromethylpurine

[0338] dd.6-Cyclopropylamino-9-(3,4-dimethoxybenzyl)-2-trifluoromethylpurine

[0339] ee.6-Cyclopropylamino-9-(2,4-dichlorobenzyl)-2-trifluoromethylpurine

[0340] ff.6-Cyclopropylamino-9-(2,3-dichlorobenzyl)-2-trifluoromethylpurine

[0341] gg.6-Cyclopropylamino-9-(3,4-ethylenedioxybenzyl)-2-trifluoromethylpurine

[0342] hh.6-Cyclopropylamino-9-(3,4-methylenedioxybenzyl)-2-trifluoromethylpurine

[0343] ii.6-Cyclopropylamino-9-(4-isopropylbenzyl)-2-trifluoromethylpurine

[0344] jj.6-Cyclopropylamino-9-(3-thienylmethyl)-2-trifluoromethylpurine

[0345] kk.6-Cyclopropylamino-9-(2-thienylmethyl)-2-trifluoromethylpurine

[0346] ll. 6-Cyclopropylamino-9-(2-furylmethyl)-2-trifluoromethylpurine

[0347] mm. 6-Cyclopropylamino-9-(3-furylmethyl)-2-trifluoromethylpurine

[0348] nn.6-Cyclopropylamino-9-[-(2-(2-chlorophlenyl)ethyl)]-2-trifluoromethylpurine

[0349] oo.6-Cyclopropylamino-9-[1-(2-(2-fluorophenyl)ethyl)]-2-trifluorometuylpurine

[0350] pp.6-Cyclopropylamino-9-[1-(2-(2-toluyl)ethyl)]-2-trifluoromethylpurine

[0351] qq.6-Cyclopropylamino-9-[1-(2-(3-chlorophenyl)ethyl)]-2-trifluoromethylpurine

[0352] rr.6-Cyclopropylamino-9-[1-(2-(3-toluyl)ethyl)]-2-trifluoromethylpurine

[0353] ss.6-Cyclopropylamino-9-[1-(2-(3-methoxyphenyl)ethyl)]-2-trifluoromethylpurine

[0354] tt.6-Cyclopropylamino-9-[1-(2-(4-chlorophenyl)ethyl)]-2-trifluoromethylpurine

[0355] uu.6-Cyclopropylamino-9-[1-(2-(4-toulyl)ethyl)]-2-trifluoromethylpurine

[0356] vv.6-Cyclopropylamino-9-[1-(2-(4-methoxyphenyl)ethyl)]-2-trifluoromethylpurine

[0357] ww.6-Cyclopropylamino-9-[1-(3-(2-methoxyphenyl)propyl)]-2-trifluoromethylpurine

[0358] xx.6-Cyclopropylamino-9-[1-(3-(4-chlorophenyl)propyl)]-2-trifluoromethylpurine

[0359] yy.6-Cyclopropylamino-9-[1-(3-(4-methoxyphenyl)propyl)]-2-trifluoromethylpurine

[0360] zz.6-Cyclopropylamino-9-(3-benzyloxybenzyl)-2-trifluoromethylpurine

[0361] aaa.6-Cyclopropylamino-9-(2,6-difluorobenzyl)-2-trifluoromethylpurine

[0362] bbb. 6-Cyclopropylamino-9-cyclopentyl-2-trifluoromethylpurine

[0363] ccc. 6-Cyclopropylamino-9-(1-propyl)-2-trifluoromethylpurine

[0364] ddd.6-Cyclopropylamino-9-(2,3-difluorobenzyl)-2-trifluoromethylpurine

[0365] eee.6-Cyclopropylamino-9-(4-fluorobenzyl)-2-trifluoromethylpurine

[0366] fff.6-Cyclopropylamino-9-(2-chlorobenzyl)-2-trifluoromethylpurine

[0367] ggg.6-Cyclopropylamino-9-(3-methylbenzyl)-2-trifluoromethylpurine

[0368] hhh.6-Cyclopropylamino-9-(2-chloro-4-fluorobenzyl)-2-trifluoromethylpurine

[0369] iii.6-Cyclopropylamino-9-[1-(2-methoxyethyl)]-2-trifluoromethylpurine

[0370] jjj. 6-Cyclopropylamino-9-(2-butyl)-2-trifluoromethylpurine

[0371] kkk. 6-Cyclopropylamino-9-(1-butyl)-2-trifluoromethylpurine

[0372] lll.6-Cyclopropylamino-9-(2-methylbenzyl)-2-trifluoromethylpurine

[0373] mmm.6-Cyclopropylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine

[0374] nnn.6-Cyclopropylamino-9-(2,4-difluorobenzyl)-2trifluoromethylpurine

[0375] ooo. 6-Cyclopropylamino-9-(2-nitrobenzyl)-2-trifluoromethylpurine

[0376] ppp. 6-Cyclopropylamino-9-benzyl-2-trifluoromethylpurine

[0377] qqq. 6-Cyclopropylamino-9-(2-propyl)-2-trifluoromethylpurine

[0378] rrr.6-Cyclopropylamino-9-(2-trifluromethylbenzyl)-2-trifluoromethylpurine

[0379] sss.6-Cyclopropylamino-9-(3-fluorobenzyl)-2-trifluoromethylpurine

[0380] ttt.6-Cyclopropylamino-9-(4-phenylbenzyl)-2-trifluoromethylpurine

[0381] uuu.6-Cyclopropylamino-9-(2-phenylbenzyl)-2-trifluoromethylpurine

[0382] vvv. 6-Cyclopropylamino-9-cyclohexyl-2-trifluoromethylpurine

[0383] www. 6-Cyclopropylamino-9-cycloheptyl-2-trifluoromethylpurine

[0384] The following compounds can be prepared in a manner similar tothat described in Example 6 using cesium carbonate rather than potassiumcarbonate:

[0385] a.6-Cyclopropylamino-9-(2,6-dichloro-4-pyridylmethyl)-2-trifluoromethylpurine

[0386] b. 6-Cyclopropylamino-9-(4-methoxybenzyl)-2-trifluoromethylpurine

[0387] c. 6-Cyclopropylamino-9-(3-nitrobenzyl)-2-trifluoromethylpurine

[0388] d. 6-Cyclopropylamino-9-(2-pyrimidyl)-2-trifluoromethylpurine

[0389] e.6-Cyclopropylamino-9-(4-(2-diethylamino)pyrimidyl)-2-trifluoromethylpurine

[0390] f.6-Cyclopropylamino-9-(4-(2-chloro)pyrimidyl)-2-trifluoromethylpurine

[0391] g.6-Cyclopropylamino-9-(4-(2-methylthio)pyrimidyl)-2-trifluoromethylpurine

[0392] The following compounds can be prepared in a manner similar tothat above using 6-N-methylamino-2-trifluoromethylpurine as a startingmaterial:

[0393] a. 6-N-methylamino-9-cyclopentyl-2-trifluoromethylpurine

[0394] b. 6-N-methylamino-9-cycloheptyl-2-trifluoromethylpurine

[0395] The following compound can be prepared in a manner similar tothat described above using 6-N-cyclopentylamino-2-trifluoromethylpurineas a starting material:

[0396] a. 6-N-cyclopentylamino-9-methyl-2-trifluoromethylpurine.

EXAMPLE 7

[0397] 6-Cyclopropylamino-9-(3-aminophenyl)-2-trifluoromethylpurine

[0398] A mixture of6-Cyclopropylamino-9-(3-nitrophenyl)-2-trifluoromethylpurine (0.1 mmol),palladium on active carbon (0.001 mol) methanol (50 ml) and acetic acid(3 ml) was shaken under 30 psi hydrogen. After 5 hours, the reactionmixture was filtered through celite and the filtrate was concentrated invacuo. The resultant residue was dissolved in 30 ml of ethyl acetate,washed with 30 mL of aqueous 5% sodium bicarbonate, concentrated andpurified by chromatography over SiO₂ to give the amino product inquantitative yield. ¹H NMR (300 MHz, CDCl₃) □ 8.10 (s, 1H), 7.27 (t,J=8.1 Hz, 1H), 7.05 (s, 1H), 6.98 (d, J=8.1 Hz, 1H), 6.70 (d, J=8.1 Hz,1H), 6.35(b, 1H), 3.18 (b, 1H), 0.91 (m, 2H), 0.69 (m, 2H).

[0399] The following compounds can be made in a similar manner:

[0400] 6-Cyclopropylamino-9-(3-aminobenzyl)-2-trifluoromethylpurine

EXAMPLE 8

[0401] 6-Cyclopropylamino-9-cyclopentyl-2-trifluoromethylpurine(Pragnacharyulu, P. V. P.; Varkhedkar, V.; Curtis, M. A.; Chang, I. F.;Abushanab, E., J. Med. Chem., 2000, 43, 4694-4700).

[0402] To a solution of 20 mg (0.08 mmol)6-cyclopropylamino-2-trifluoromethylpurine, 42 mg (0.16 mmol) of PPh₃,and 18 mg (0.21 mmol) cyclopentanol in THF under N₂ atmosphere withmagnetic stirring, was added 48 mg (0.23 mmol) DIAD. The resultingmixture was stirred at room temperature for 16 hours, concentrated,taken up in 10 mL H₂O and extracted with 2×15 mL of ether. The organiclayer was combined and dried over (MgSO₄), concentrated in vacuo, andpurified by chromatography over silica gel using 10% MeOH in CH₂Cl₂ togive the desired product. ¹H NMR (CDCl₃) 7.92 (s, 1H), 6.01 (bs, 1H),4.98 (p, 1H), 3.18 (bs, 1H), 2.36-2.25 (m, 2H), 2.03-1.79 (m, 6H), 0.86(dd, 2H), 0.65 (dd, 2H).

[0403] The following compounds were prepared in a similar manner:

[0404] a. 6-Cyclopropylamino-9-cyclopentylmethyl-2-trifluoromethylpurine

[0405] b. 6-Cyclopropylamino-9-cyclopentylethyl-2-trifluoromethylpurine

[0406] c. 6-Cyclopropylamino-9-cyclopentylpropyl-2-trifluoromethylpurine

[0407] d.6-Cyclopropylamino-9-(3-(1-ethyl-pyrrolidinyl)-2-trifluoromethylpurine

[0408] e.6-Cyclopropylamino-9-(3-(1-ethyl-piperidinyl)-2-trifluoromethylpurine

[0409] f.6-Cyclopropylamino-9-(2-(1-ethyl-piperidinyl)-2-trifluoromethylpurine

[0410] g.6-Cyclopropylamino-9-(piperidin-1-ylethyl)-2-trifluoromethylpurine

[0411] h.6-Cyclopropylamino-9-(2-(1-methyl-piperidinyl)-2-trifluoromethylpurine

[0412] i.6-Cyclopropylamino-9-(5-oxo-(S)-pyrrolidin-3-yl)-2-trifluoromethylpurine

[0413] j.6-Cyclopropylamino-9-(5-oxo-(R)-pyrrolidin-3-yl)-2-trifluoromethylpurine

EXAMPLE 9

[0414]6-Cyclopropylamino-9-(3,4-dimethoxyphenyl)-2-trifluoromethylpurine

[0415] A mixture of 6-cyclopropylamino-2-trifluoromethyladenine (46 mg,0.2 mmol), 3,4-dimethoxyphenyl boronic acid (44 mg, 0.24 mmol),copper(II) acetate (36 mg, 0.2 mmol), triethylamine (1.0 mmol, 101 mg),anhydrous acetonitrile (4 ml) and molecular seives (˜10 pellets) wasstirred at 50-55° C. for 18 hours. Ethyl acetate (20 ml) was added andthe solid was removed by filtration. The filtrate was washed with 20 mlof 5% 1sodium bicarbonate aqueous solution. Evaporation andchromatography over SiO₂ using hexane/ethylacetate/methanol (50:50:1) aselunt gave 7.9 mg of the title compound (yield 10%). ¹H NMR (300 MHz,CDCl₃) δ 8.10 (s, 1H), 7.39 (s, 1H), 7.13 (d, J=8.7 Hz, 2H), 6.98 (d,J=8.7 Hz, 2H), 6.35(b, 1H), 3.93 (s, 3H), 3.90 (s, 3H), 3.18 (b, 1H),0.91 (m, 2H), 0.69 (m, 2H)

[0416] The following compounds were prepared in a similar manner:

[0417] a.6-Cyclopropylamino-9-(3,4-dimethoxyphenyl)-2-trifluoromethylpurine

[0418] b. 6-Cyclopropylamino-9-(3-methoxyphenyl)-2-trifluoromethylpurine

[0419] c. 6-Cyclopropylamino-9-(4-methoxyphenyl)-2-trifluoromethylpurine

[0420] d. 6-Cyclopropylamino-9-(3-nitrophenyl)-2-trifluoromethylpurine

[0421] e. 6-Cyclopropylamino-9-(2-methoxyphenyl)-2-trifluoromethylpurine

[0422] f. 6-Cyclopropylamino-9-(3-cyanophenyl)-2-trifluoromethylpurine

[0423] e.6-Cyclopropylamino-9-(2,5-dimethoxphenyl)-2-trifluoromethylpurine

[0424] h.6-Cyclopropylamino-9-(2,4-dimethoxypyrimidyl)-2-trifluoromethylpurine

[0425] i.6-Cyclopropylamino-9-(2-methoxy-5-pyridyl)-2-trifluoromethylpurine

[0426] j. 6-Cyclopropylamino-9-(4-pyridyl)-2-trifluoromethylpurine

[0427] k. 6-Cyclopropylamino-9-(3-pyridyl)-2-trifluoromethylpurine

[0428] l.6-Cyclopropylamino-9-(1-tert-butoxycarbonyl-pyrrol-2-yl)-2-trifluoromethylpurine

[0429] m.6-Cyclopropylamino-9-(4-dimethylaminophenyl)-2-trifluoromethylpurine

[0430] n.6-Methylamino-9-(2,4-dimethoxy-5-pyrimidyl)-2-trifluoromethylpurine

[0431] o. 6-Methylamino-9-(2-methoxyphenyl)-2-trifluoromethylpurine

[0432] p. 6-Methylamino-9-(4-methoxyphenyl)-2-trifluoromethylpurine

[0433] q. 6-Methylamino-9-(3-acetylphenyl)-2-trifluoromethylpurine

[0434] r. 6-Methylamino-9-(3-methoxyphenyl)-2-trifluoromethylpurine

[0435] s. 6-Methylamino-9-(3-nitrophenyl)-2-trifluoromethylpurine

[0436] t. 6-Cyclopropylamino-9-(3-furanyl)-2-trifluoromethylpurine

[0437] u. 6-Cyclopropylamino-9-(4-ethoxyphenyl)-2-trifluoromethylpurine

[0438] v. 6-Cyclopropylamino-9-(2-ethoxyphenyl)-2-trifluoromethylpurine

[0439] w.6-Cyclopropylamino-9-(3,4-methylenedioxyphenyl)-2-trifluoromethylpurine

[0440] x. 6-Cyclopropylamino-9-(3-ethoxyphenyl)-2-trifluoromethylpurine

[0441] y. 6Methylamino-9-(3,4-dimethoxyphenyl)-2-trifluoromethylpurine

[0442] z.6-Cyclopropylamino-9-(3,5-dimethoxyphenyl)-2-trifluoromethylpurine

[0443] aa.6-Cyclopropylamino-9-(2-methoxy-5-chlorophenyl)-2-trifluoromethylpurine

[0444] bb. 6-Cyclopropylamino-9-phenyl-2-trifluoromethylpurine

[0445] cc. 6-Cyclopropylamino-9-(2-fluorophenyl)-2-trifluoromethylpurine

[0446] dd. 6-Cyclopropylamino-9-(4-fluorophenyl)-2-trifluoromethylpurine

[0447] ee. 6-Cyclopropylamino-9-(4-chlorophenyl)-2-trifluoromethylpurine

[0448] ff. 6-Cyclopropylamino-9-(4-toluyl)-2-trifluoromethylpurine

[0449] gg.6-Cyclopropylamino-9-(4-trifluoromethylphenyl)-2-trifluoromethylpurine

[0450] hh. 6-Cyclopropylamino-9-(3-thienyl)-2trifluoromethylpurine

[0451] ii.6-Cyclopropylamino-9-(3-trifluoromethylphenyl)-2-trifluoromethylpurine

EXAMPLE 10 In Vitro Measurement of Type 4 Phosphodiesterase InhibitionActivity

[0452] Human PDE4 was obtained from baculovirus-infected Sf9 cells thatexpressed the recombinant enzyme. The cDNA encoding hPDE-4D6 wassubcloned into a baculovirus vector. Insect cells (Sf9) were infectedwith the baculovirus and cells were cultured until protein wasexpressed. The baculovirus-infected cells were lysed and the lysate wasused as source of hPDE-4D6 enzyme. The enzyme was partially purifiedusing a DEAE ion exchange chromatography. This procedure can be repeatedusing cDNA encoding other PDE-4 enzymes.

[0453] Assay:

[0454] Type 4 phosphodiesterases convert cyclic adenosine monophosphate(cAMP) to 5′-adenosine monophosphate (5′-AMP). Nucleotidase converts5′-AMP to adenosine. Therefore the combined activity of PDE4 andnucleotidase converts cAMP to adenosine. Adenosine is readily separatedfrom cAMP by neutral alumina columns. Phosphodiesterase inhibitors blockthe conversion of cAMP to adenosine in this assay; consequently, PDE4inhibitors cause a decrease in adenosine.

[0455] Cell lysates (40 ul) expressing hPDE-4D6 were combined with 50 ulof assay mix and 10 ul of inhibitors and incubated for 12 min at roomtemperature. Final concentrations of assay components were: 0.4 ugenzyme, 10 mM Tris-HCl (pH 7.5), 10 mM MgCl₂, 3 uM cAMP, 0.002 U5′-nucleotidase, and 3×10⁴ cpm of [3H]cAMP. The reaction was stopped byadding 100 μl of boiling 5 mN HCl. An aliquot of 75 μl of reactionmixture was transferred from each well to alumina columns (Multiplate;Millipore). Labeled adenosine was eluted into an OptiPlate by spinningat 2000 rpm for 2 min; 150 μl per well of scintillation fluid was addedto the OptiPlate. The plate was sealed, shaken for about 30 min, and cpmof [³H]adenosine was determined using a Wallac Trilux®.

[0456] All test compounds are dissolved in 100% DMSO and diluted intothe assay such that the final concentration of DMSO is 0.1%. DMSO doesnot affect enzyme activity at this concentration.

[0457] A decrease in adenosine concentration is indicative of inhibitionof PDE activity. pIC₅₀ values were determined by screening 6 to 12concentrations of compound ranging from 0.1 nM to 10,000 nM and thenplotting drug concentration versus ³H-adenosine concentration. Nonlinearregression software (Assay Explorer) was used to estimate pIC₅₀ values.

EXAMPLE 11 Passive Avoidance in Rats, an in vivo Test for Learning andMemory

[0458] The test was performed as previously described (Zhang, H. -T.,Crissman, A. M., Dorairaj, N. R., Chandler, L. J., and O'Donnell, J. M.,Neuropsychopharmacology, 2000, 23, 198-204.). The apparatus (ModelE10-16SC, Coulbourn Instruments, Allentown, Pa.) consisted of atwo-compartment chamber with an illuminated compartment connected to adarkened compartment by a guillotine door. The floor of the darkenedcompartment consisted of stainless steel rods through which an electricfoot-shock could be delivered from a constant current source. Allexperimental groups were first habituated to the apparatus the daybefore the start of the experiment. During the training, the rat (MaleSpraque-Dawley (Harlan) weighing 250 to 350 g) was placed in theilluminated compartment facing away from the closed guillotine door for1 minute before the door was raised. The latency for entering thedarkened compartment was recorded. After the rat entered the darkenedcompartment, the door was closed and a 0.5 mA electric shock wasadministered for 3 seconds. Twenty-four hours later, the rat wasadministered 0.1 mg/kg MK-801 or saline, 30 minutes prior to theinjection of saline or test compound (dosed from 0.1 to 2.5 mg/kg,i.p.), which was 30 minutes before the retention test started. The ratwas again placed in the illuminated compartment with the guillotine dooropen. The latency for entering the darkened compartment was recorded forup to 180 seconds, at which time the trial was terminated.

[0459] All data were analyzed by analyses of variance (ANOVA);individual comparisons were made using Kewman-Keuls tests. Naive ratsrequired less than 30 seconds, on average, to cross from the illuminatedcompartment to the darkened compartment. However, 24 hours after theelectric shock exposure, most rats pretreated with vehicle did notre-enter the darkened compartment; the average latency was increased upto 175 seconds (p<0.001). Pretreatment with MK-801 (0.1 mg/kg) markedlyreduced this latency when compared to the vehicle (p<0.001). Thisamnesic effect of MK-801 is reversed in a statistically significantmanner by actual test compounds in a dose-dependent fashion.

EXAMPLE 12 Radial Arm Maze Task in Rats, an in vivo Test for Learningand Memory

[0460] The test was performed as previously described (Zhang, H. -T.,Crissman, A. M., Dorairaj, N. R., Chandler, L. J., and O'Donnell, J. M.,Neuropsychopharmacology, 2000, 23, 198-204.). Five days after initialhousing, rats (male Spraque-Dawley (Harlan) weighing 250 to 350 g) wereplaced in the eight-arm radial maze (each arm was 60×10×12 cm high; themaze was elevated 70 cm above the floor) for acclimation for two days.Rats were then placed individually in the center of the maze for 5minutes with food pellets placed close to the food wells, and then, thenext day, in the wells at the end of the arms; 2 sessions a day wereconducted. Next, four randomly selected arms were then baited with onepellet of food each. The rat was restricted to the center platform (26cm in diameter) for 15 seconds and then allowed to move freelythroughout the maze until it collected all pellets of food or 10 minutespassed, whichever came first. Four parameters were recorded: 1) workingmemory errors, i.e., entries into baited arms that had already beenvisited during the same trial; 2) reference memory errors, i.e., entriesinto unbaited arms; 3) total arm entries; and 4) the test duration(seconds), i.e., the time spent in the collection of all the pellets inthe maze. If the working memory error was zero and the average referencememory error was less than one in five successive trials, the rats beganthe drug tests. MK-801 or saline was injected 15 minutes prior tovehicle or test agent, which was given 45 minutes before the test.Experiments were performed in a lighted room, which contained severalextra-maze visual cues.

[0461] All data were analyzed by analyses of variance (ANOVA);individual comparisons were made using Kewman-Keuls tests. Compared tocontrol, MK-801 (0.1 mg/kg, i.p.) increased the -frequencies of bothworking and reference memory errors (p<0.01). This amnesic effect ofMK-801 on working memory is reversed in a statistically significantmanner by the administration of actual test compounds in adose-dependent fashion.

[0462] The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

[0463] While the invention has been illustrated with respect to theproduction and of particular compounds, it is apparent that variationsand modifications of the invention can be made without departing fromthe spirit or scope of the invention.

What is claimed is:
 1. A compound of Formula I:

wherein, R¹ is H, alkyl having 1 to 5 carbon atoms, which isunsustituted or substituted one or more times by halogen, hydroxy, orcombinations thereof, and wherein a —CH₂— group can be optionallyreplaced by —O—, —S—, or —NH—, cycloalkyl having 3 to 6 carbon atoms, orcycloalkylalkyl having 4 to 7 C atoms; R² is alkyl having 1 to 12 carbonatoms, which is unsubstituted or substituted one or more times byhalogen, hydroxy, cyano or combinations thereof, wherein one or more—CH₂— groups is each independently optionally replaced by —O—, —S—, or—NH—, and wherein optionally one or more —CH₂CH₂— groups is replaced ineach case by —CH═CH— or —C≡C—, alkyl ether having 3 to 12 carbon atoms,cycloalkyl having 3 to 12 carbon atoms, which is unsubstituted orsubstituted one or more times by halogen, C₁₋₄ alkyl, halogenated C₁₋₄alkyl, C₁₋₄ alkoxy, cyano or combinations thereof, cycloalkylalkylhaving 4 to 12 C atoms, which is unsubstituted or substituted one ormore times by C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano,halogen, or combinations thereof, aryl having 6 to 14 carbon atoms,which is unsubstituted or substituted one or more times by halogen, C₁₋₄alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy,cyano, hydroxamic acid, carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof, arylalkyl having 7 to 16 carbon atoms, which isunsubstituted or substituted one or more times by halogen, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy,nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy,cyano, hydroxamic acid, carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof, heteroaryl having 5 to 10 ring atoms in which atleast 1 ring atom is a heteroatom, which is unsubstituted or substitutedone or more times by halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl,hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl,nitro, oxo, amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy,alkoxycarbonyl, hydroxamic acid, carboxamide, C₁₋₄-alkylthio,C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, or combinations thereof,heteroarylalkyl wherein the heteroaryl portion has 5 to 10 ring atoms inwhich at least 1 ring atom is a heteroatom and the alkyl portion has 1to 3 carbon atoms, the heteroaryl portion is unsubstituted or issubstituted one or more times in by halogen, aryl, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy,cyano, trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid,carboxamide, C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl,or combinations thereof, heterocycle having 5 to 10 ring atoms in whichat least 1 ring atom is a heteroatom, which is unsubstituted or issubstituted one or more times in the by halogen, aryl, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy,cyano, trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, or combinations thereof,heterocycle-alkyl wherein the heterocycle portion has 5 to 10 ring atomsin which at least 1 ring atom is a heteroatom and the alkyl portion has1 to 3 carbon atoms, the heterocycle portion is nonarmoatic and isunsubstituted or is substituted one or more times in the by halogen,aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy,halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl, nitro, oxo, amino,C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, orcombinations thereof, or carbocycle which is nonaromatic, monocyclic orbicyclic, group having 5 to 14 carbon atoms, which is unsubstituted oris substituted one or more times in the by halogen, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy,nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy,cyano, hydroxamic acid, carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof; and pharmaceutically acceptable salts thereof,with the provisos that: (a) when R¹ is methyl, then R² is not arylalkyl,heteroarylalkyl, 2-(1,2,3,4-tetrahydro)quinolinyl-methyl, methyl or2-butyl; (b) when R¹ is cyclopropyl, R² is not 4-methylbenzyl; (c) whenR¹ is ethyl, then R² is not ethyl, 3-aminobenzyl, 2-thienylmethyl,3-thienyhnethyl, or 2-pyridylmethyl; (d) when R¹ is cyclopropyl, then R²is not cyclopropylmethyl; (e) when R¹ is H, then R² is not methyl,ethyl, benzyl, 4-methylbenzyl, or substituted tetrahydrofuranyl; (f)when R¹ is methoxyethyl, then R² is not benzyl, 3-dimethylaminobenzyl,or 3-thienylmethyl; (g) when R¹ is iso-butyl, then R² is not benzyl; and(h) when R¹ is n-butyl, then R² is not n-butyl.
 2. A compound accordingto claim 1, wherein when R¹ is methyl, R² is not arylalkyl,heteroarylalkyl, 2-(1,2,3,4-tetrahydro)quinolinyl-methyl or C₁₋₅-alkyl.3. A compound according to claim 1, wherein R¹ is alkyl.
 4. A compoundaccording to claim 1, wherein R¹ is cycloalkyl.
 5. A compound accordingto claim 1, wherein R¹ is cycloalkylalkyl.
 6. A compound according toclaim 1, wherein R² is alkyl.
 7. A compound according to claim 1,wherein R² is alkyl ether.
 8. A compound according to claim 1, whereinR² is cycloalkyl.
 9. A compound according to claim 1, wherein R² isaryl.
 10. A compound according to claim 1, wherein R² is arylalkyl. 11.A compound according to claim 1, wherein R² is heteroaryl.
 12. Acompound according to claim 1, wherein R² is heteroarylalkyl.
 13. Acompound according to claim 1, wherein R² heterocycle.
 14. A compoundaccording to claim 1, wherein R² heterocycle-alkyl.
 15. A compoundaccording to claim 1, wherein R² carbocycle.
 16. A compound according toclaim 1, wherein R¹ is alkyl, substituted alkyl, cycloalkyl orcycloalkylalkyl.
 17. A compound according to claim 6, wherein R¹ isalkyl, cycloalkyl or cycloalkylalkyl.
 18. A compound according to claim7, wherein R¹ is alkyl, cycloalkyl or cycloalkylalkyl.
 19. A compoundaccording to claim 8, wherein R¹ is alkyl, cycloalkyl orcycloalkylalkyl.
 20. A compound according to claim 9, wherein R¹ isalkyl, cycloalkyl or cycloalkylalkyl.
 21. A compound according to claim10, wherein R¹ is alkyl, cycloalkyl or cycloalkylalkyl.
 22. A compoundaccording to claim 11, wherein R¹ is alkyl, cycloalkyl orcycloalkylalkyl.
 23. A compound according to claim 12, wherein R¹ isalkyl, cycloalkyl or cycloalkylalkyl.
 24. A compound according to claim13, wherein R¹ is alkyl, cycloalkyl or cycloalkylalkyl.
 25. A compoundaccording to claim 14, wherein R¹ is alkyl, cycloalkyl orcycloalkylalkyl.
 26. A compound according to claim 15, wherein R¹ isalkyl, cycloalkyl or cycloalkylalkyl.
 27. A compound according to claim1, wherein R¹ is methyl, ethyl, isopropyl, 2-hydroxyethyl, cyclopropyl,cyclopentyl, or cyclopropylmethyl.
 28. A compound according to claim 1,wherein R¹ is methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl.
 29. A compound according to claim 1, wherein R¹ is methyl,ethyl or cyclopropyl.
 30. A compound according to claim 1, wherein R² isalkyl, arylalkyl, cycloalkyl, aryl, heteroaryl, heteroarylalkyl, oralkyl ether.
 31. A compound according to claim 1, wherein R² is ethyl,isopropyl, butyl, tert-butyl, cyclopentyl, cyclohexyl, cycloheptyl, orarylalkyl which is unsubstituted or substituted one or more times by F,Cl, CN, CF₃, CH₃, C₂H₅, isopropyl, OCH₃, methylenedioxy, ethylenedioxyor combinations thereof.
 32. A compound according to claim 1, wherein R²is substituted or unsubstituted benzyl, phenethyl or phenpropyl.
 33. Acompound of formula II

wherein R¹′ is methyl, ethyl, or cyclopropyl; and R²′ is cycloalkylhaving 3 to 12 carbon atoms, which is unsubstituted or substituted oneor more times by halogen, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, C₁₋₄alkoxy, cyano or combinations thereof, aryl having 6 to 14 carbon atoms,which is unsubstituted or substituted one or more times by halogen, C₁₋₄alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy,cyano, hydroxamic acid, carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof, heteroaryl having 5 to 10 ring atoms in which atleast 1 ring atom is a heteroatom, which is unsubstituted or substitutedone or more times by halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl,hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl,nitro, oxo, amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy,alkoxycarbonyl, hydroxamic acid, carboxamide, C₁₋₄-alkylthio,C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, or combinations thereof,heterocycle having 5 to 10 ring atoms in which at least 1 ring atom is aheteroatom, which is unsubstituted or is substituted one or more timesin the by halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy,C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl, nitro,oxo, amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy,alkoxycarbonyl, or combinations thereof (e.g., piperidinyl,imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl,piperazinyl, and indolinyl), or carbocycle which is nonaromatic,monocyclic or bicyclic, group having 5 to 14 carbon atoms, which isunsubstituted or is substituted one or more times in the by halogen,C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenatedC₁₋₄ alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄alkylamino, di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy,carboxy, cyano, hydroxamic acid, carboxamide, C₂₋₄-acyl,C₂₋₄-alkoxycarbonyl, C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl,C₁₋₄-alkylsulphonyl, phenoxy, or combinations thereof; andpharmaceutically acceptable salts thereof.
 34. A compound of FormulaIII:

wherein R¹″ is methyl, ethyl, or cyclopropyl; and R²″ is phenyl, phenylwhich is substituted one or more times by halogen, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, nitro, methylenedioxy,ethylenedioxy, amino, Cl, 4 alkylamino, di-C₁₋₄-alkylamino,C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy, cyano, C₂₋₄-acyl,C₂₋₄-alkoxycarbonyl, C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl,C₁₋₄-alkylsulphonyl, phenoxy, or combinations thereof, or heteroarylhaving 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom,substituted heteroaryl having 5 to 10 ring atoms, in which at least 1ling atom is a heteroatom, which is unsubstituted or substituted one ormore times by halogen, aryl, C₁₋₄-alkyl, C₁₋₄-alkoxy, cyano,trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylaminoor combinations thereof, or when R¹ is methyl or cyclopropyl R² can alsobe cycloalkyl having 3 to 12 carbon atoms; and pharmaceuticallyacceptable salts thereof.
 35. A compound according to claim 1, whereinsaid compound selected from:6-Cyclopropylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine6-Ethylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-fluorobenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(2,6-difluorobenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(2,3-difluorobenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-propyl 2-trifluoromethylpurine6-Cyclopropylamino-9-cyclopentyl-2-trifluoromethylpurine6-Cyclopropylamino-9-(3,4-dimethoxybenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3,4-methylenedioxybenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-thiophenemethyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(2-methylphenethyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-cycloheptyl-2-trifluoromethylpurine6-Methylamino-9-cyclopentyl-2-trifluoromethylpurine6-Cyclopropylamino-9-cyclohexyl-2-trifluoromethylpurine6-Methylamino-9-cycloheptyl-2-trifluoromethylpurine6-Cyclopropylamino-9-cyclopentylmethyl-2-trifluoromethylpurine6-Cyclopropylamino-9-phenyl-2-trifluoromethylpurine6-Cyclopropylamino-9-(2-fluorophenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-cyclobutyl-2-trifluoromethylpurine6-Cyclopropylamino-9-(2-norboranane)-2-trifluoromethylpurine6-Cyclopropylamino-9-(1-indanyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-fluorophenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-chlorophenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-thienyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-cyclopentyloxy-4-methoxybenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3,4-dimethoxyphenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(2,6-dichloro-4-pyridylmethyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-methoxybenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-methoxyphenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-methoxyphenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-nitrophenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(2-methoxyphenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-cyanophenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(2,4-dimethoxyphenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-nitrobenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(6-methoxy-3-pyridyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-pyridyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-pyridyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-dimethylaminophenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-aminophenyl)-2-trifluoromethylpurine6-Methylamino-9-(2,4-dimethoxy-5-pyrimidyl)-2-trifluoromethylpurine6-Methylamino-9-(2-methoxyphenyl)-2-trifluoromethylpurine6-Methylamino-9-(4-methoxyphenyl)-2-trifluoromethylpurine6-Methylamino-9-(3-acetylphenyl)-2-trifluoromethylpurine6-Methylamino-9-(3-methoxyphenyl)-2-trifluoromethylpurine6-Methylamino-9-(3-nitrophenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-furanyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-ethoxyphenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(2-ethoxyphenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3,4-methylenedioxyphenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-ethoxyphenyl)-2-trifluoromethylpurine6-Methylamino-9-(3,4-dimethoxyphenyl)-2-trifluoromethylpurine; andpharmaceutically acceptable salts thereof.
 36. A compound according toclaim 34, wherein said compound selected from:6-Cyclopropylamino-9-(2,3-difluorobenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-cyclopentyl-2-trifluoromethylpurine6-Cyclopropylamino-9-(3,4-dimethoxybenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-cycloheptyl-2-trifluoromethylpurine6-Methylamino-9-cyclopentyl-2-trifluoromethylpurine6-Cyclopropylamino-9-cyclohexyl-2-trifluoromethylpurine6-Methylamino-9-cycloheptyl-2-trifluoromethylpurine6-Cyclopropylamino-9-phenyl-2-trifluoromethylpurine6-Cyclopropylamino-9-(2-fluorophenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-cyclobutyl-2-trifluoromethylpurine6-Cyclopropylamino-9-(2-norboranane)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-fluorophenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-chlorophenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-thienyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3,4-dimethoxyphenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(2,6-dichloro-4-pyridylmethyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-methoxybenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-methoxyphenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-methoxyphenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-nitrophenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(2-methoxyphenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-cyanophenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-nitrobenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-pyridyl)-2-trifluoromethylpurine6-Methylamino-9-(2,4-dimethoxy-5-pyrimidyl)-2-trifluoromethylpurine6-Methylamino-9-(4-methoxyphenyl)-2-trifluoromethylpurine6-Methylamino-9-(3-acetylphenyl)-2-trifluoromethylpurine6-Methylamino-9-(3-methoxyphenyl)-2-trifluoromethylpurine6-Methylamino-9-(3-nitrophenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-ethoxyphenyl)-2-trifluoromethylpurine6-Methylamino-9-(3,4-dimethoxyphenyl)-2-trifluoromethylpurine; andpharmaceutically acceptable salts thereof.
 37. A method for enhancingcognition in a patient in whom such enhancement is desired comprisingadministering to said patient an effective amount of a compoundaccording to formula I^(c):

wherein, R^(1c) is H, alkyl having 1 to 5 carbon atoms, which isunsustituted or substituted one or more times by halogen, hydroxy, orcombinations thereof, and wherein a —CH₂— group can be optionallyreplaced by —O—, —S—, or —NH—, cycloalkyl having 3 to 6 carbon atoms, orcycloalkylalkyl having 4 to 7 C atoms; R^(2c) is alkyl having 1 to 12carbon atoms, which is unsubstituted or substituted one or more times byhalogen, hydroxy, cyano or combinations thereof, wherein one or more—CH₂— groups is each independently optionally replaced by —O—, —S—, or—NH—, and wherein optionally one or more —CH₂CH₂— groups is replaced ineach case by —CH═CH— or —C≡C— alkyl ether having 3 to 12 carbon atoms,cycloalkyl having 3 to 12 carbon atoms, which is unsubstituted orsubstituted one or more times by halogen, C₁₋₄ alkyl, halogenated C₁₋₄alkyl, C₁₋₄ alkoxy, cyano or combinations thereof, cycloalkylalkylhaving 4 to 12 C atoms, which is unsubstituted or substituted one ormore times by C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano,halogen, or combinations thereof, aryl having 6 to 14 carbon atoms,which is unsubstituted or substituted one or more times by halogen, C₁₋₄alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy,cyano, hydroxamic acid, carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof, arylalkyl having 7 to 16 carbon atoms, which isunsubstituted or substituted one or more times by halogen, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy,nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy,cyano, hydroxamic acid, carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof, heteroaryl having 5 to 10 ring atoms in which atleast 1 ring atom is a heteroatom, which is unsubstituted or substitutedone or more times by halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl,hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl,nitro, oxo, amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy,alkoxycarbonyl, hydroxamic acid, carboxamide, C₁₋₄-alkylthio,C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl,or combinations thereof,heteroarylalkyl wherein the heteroaryl portion has 5 to 10 ring atoms inwhich at least 1 ring atom is a heteroatom and the alkyl portion has 1to 3 carbon atoms, the heteroaryl portion is unsubstituted or issubstituted one or more times in by halogen, aryl, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy,cyano, trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid,carboxamide, C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl,or combinations thereof, heterocycle having 5 to 10 ring atoms in whichat least I ring atom is a heteroatom, which is unsubstituted or issubstituted one or more times in the by halogen, aryl, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy,cyano, trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, or combinations thereof,heterocycle-alkyl wherein the heterocycle portion has 5 to 10 ring atomsin which at least 1 ring atom is a heteroatom and the alkyl portion has1 to 3 carbon atoms, the heterocycle portion is nonarmoatic and isunsubstituted or is substituted one or more times in the by halogen,aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy,halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl, nitro, oxo, amino,C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, orcombinations thereof, or carbocycle which is nonaromatic, monocyclic orbicyclic, group having 5 to 14 carbon atoms, which is unsubstituted oris substituted one or more times in the by halogen, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy,nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy,cyano, hydroxamic acid, carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof; and pharmaceutically acceptable salts thereof,with the proviso that said compound is not6-methylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine.
 38. A methodaccording to claim 37, wherein said compound is administered in anamount of 0.01-100 mg/kg of body weight/day.
 39. A method according toclaim 37, wherein said patient is a human.
 40. A method according toclaim 37, wherein said compound selected from:6-Cyclopropylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine;6-Ethylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-fluorobenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(2,6-difluorobenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(2,3-difluorobenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-propyl 2-trifluoromethylpurine6-Cyclopropylamino-9-cyclopentyl-2-trifluoromethylpurine6-Cyclopropylamino-9-(3,4-dimethoxybenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3,4-methylenedioxybenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-thiophenemethyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(2-methylphenethyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-cyclopropylmethyl-2-trifluoromethylpurine6-Cyclopropylamino-9-cycloheptyl-2-trifluoromethylpurine6-Methylamino-9-cyclopentyl-2-trifluoromethylpurine6-Cyclopropylamino-9-cyclohexyl-2-trifluoromethylpurine6-Methylamino-9-cycloheptyl-2-trifluoromethylpurine6-Cyclopropylamino-9-cyclopentylmethyl-2-trifluoromethylpurine6-Cyclopropylamino-9-phenyl-2-trifluoromethylpurine6-Cyclopropylamino-9-(2-fluorophenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-cyclobutyl-2-trifluoromethylpurine6-Cyclopropylamino-9-(2-norboranane)-2-trifluoromethylpurine6-Cyclopropylamino-9-(1-indanyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-fluorophenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-chlorophenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-tolyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-thienyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-cyclopentyloxy-4-methoxybenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3,4-dimethoxyphenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(2,6-dichloro-4-pyridylmethyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-methoxybenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-methoxyphenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-methoxyphenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-nitrophenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(2-methoxyphenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-cyanophenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(2,4-dimethoxyphenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-nitrobenzyl)-2-trifluoromethylpurine6-Cyclopropyl amino-9-(6-methoxy-3-pyridyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-pyridyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-pyridyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-dimethylaminophenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-aminophenyl)-2-trifluoromethylpurine6-Methylamino-9-(2,4-dimethoxy-5-pyrimidyl)-2-trifluoromethylpurine6-Methylamino-9-(2-methoxyphenyl)-2-trifluoromethylpurine6-Methylamino-9-(4-methoxyphenyl)-2-trifluoromethylpurine6-Methylamino-9-(3-acetylphenyl)-2-trifluoromethylpurine6-Methylamino-9-(3-methoxyphenyl)-2-trifluoromethylpurine6-Methylamino-9-(3-nitrophenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-furanyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-ethoxyphenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(2-ethoxyphenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3,4-methylenedioxyphenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-ethoxyphenyl)-2-trifluoromethylpurine6-Methylamino-9-(3,4-dimethoxyphenyl)-2-trifluoromethylpurine; andpharmaceutically acceptable salts thereof.
 41. A method according toclaim 40, wherein said patient is a human.
 42. A method according toclaim 41, wherein said compound is administered in an amount of 0.01-100mg/kg of body weight/day.
 43. A method according to claim 37, whereinwhen R^(1c) is methyl, then R^(2c) is not arylalkyl, methyl or 2-butyl,and when R^(1c) is H, then R^(2c) is not benzyl
 44. A method accordingto claim 37, wherein: (a) when R^(1c) is methyl, then R^(2c) is notarylalkyl, heteroarylalkyl, 2-(1,2,3,4-tetrahydro)quinolinyl-methyl,methyl or 2-butyl; (b) when R^(1c) is cyclopropyl, R^(2c) is not4-methylbenzyl; (c) when R^(1c) is ethyl, then R^(2c) is not ethyl,3-aminobenzyl, 2-thienylmethyl, 3-thienylmethyl, or 2-pyridylmethyl; (d)when R^(1c) is cyclopropyl, then R^(2c) is not cyclopropylmethyl; (e)when R^(1c) is H, then R^(2c) is not methyl, ethyl, benzyl,4-methylbenzyl, or substituted tetrahydrofuranyl; (f) when R^(1c) ismethoxyethyl, then R^(2c) is not benzyl, 3-dimethylaminobenzyl, or3-thienylmethyl; (g) when R^(1c) is iso-butyl, then R^(2c) is notbenzyl; and (h) when R^(1c) is n-butyl, then R^(2c) is not n-butyl. 45.A method of treating a patient suffering from cognition impairment ordecline comprising administering to said patient an effective amount ofa compound according to formula I^(c):

wherein, R^(1c) is H, alkyl having 1 to 5 carbon atoms, which isunsustituted or substituted one or more times by halogen, hydroxy, orcombinations thereof, and wherein a —CH₂— group can be optionallyreplaced by —O—, —S—, or —NH—, cycloalkyl having 3 to 6 carbon atoms, orcycloalkylalkyl having 4 to 7 C atoms; R^(2c) is alkyl having 1 to 12carbon atoms, which is unsubstituted or substituted one or more times byhalogen, hydroxy, cyano or combinations thereof, wherein one or more—CH₂— groups is each independently optionally replaced by —O—, —S—, or—NH—, and wherein optionally one or more —CH₂CH₂— groups is replaced ineach case by —CH═CH— or —C≡C— alkyl ether having 3 to 12 carbon atoms,cycloalkyl having 3 to 12 carbon atoms, which is unsubstituted orsubstituted one or more times by halogen, C₁₋₄ alkyl, halogenated C₁₋₄alkyl, C₁₋₄ alkoxy, cyano or combinations thereof, cycloalkylalkylhaving 4 to 12 C atoms, which is unsubstituted or substituted one ormore times by C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano,halogen, or combinations thereof, aryl having 6 to 14 carbon atoms,which is unsubstituted or substituted one or more times by halogen, C₁₋₄alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy,cyano, hydroxamic acid, carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof, arylalkyl having 7 to 16 carbon atoms, which isunsubstituted or substituted one or more times by halogen, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy,nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy,cyano, hydroxamic acid, carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof, heteroaryl having 5 to 10 ring atoms in which atleast 1 ring atom is a heteroatom, which is unsubstituted or substitutedone or more times by halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl,hydroxy, C₁₋₄alkoxy, halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl,nitro, oxo, amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy,alkoxycarbonyl, hydroxamic acid, carboxamide, C₁₋₄-alkylthio,C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, or combinations thereof,heteroarylalkyl wherein the heteroaryl portion has 5 to 10 ring atoms inwhich at least 1 ring atom is a heteroatom and the alkyl portion has 1to 3 carbon atoms, the heteroaryl portion is unsubstituted or issubstituted one or more times in by halogen, aryl, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy,cyano, trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid,carboxamide, C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl,or combinations thereof, heterocycle having 5 to 10 ring atoms in whichat least 1 ring atom is a heteroatom, which is unsubstituted or issubstituted one or more times in the by halogen, aryl, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy,cyano, trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, or combinations thereof,heterocycle-alkyl wherein the heterocycle portion has 5 to 10 ring atomsin which at least 1 ring atom is a heteroatom and the alkyl portion has1 to 3 carbon atoms, the heterocycle portion is nonarmoatic and isunsubstituted or is substituted one or more times in the by halogen,aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy,halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl, nitro, oxo, amino,C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, orcombinations thereof, or carbocycle which is nonaromatic, monocyclic orbicyclic, group having 5 to 14 carbon atoms, which is unsubstituted oris substituted one or more times in the by halogen, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy,nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy,cyano, hydroxamic acid, carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof; and pharmaceutically acceptable salts thereof,with the proviso that said compound is not6-methylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine.
 46. A methodaccording to claim 45, wherein said patient is a human.
 47. A methodaccording to claim 46, wherein said patient is suffering from memoryimpairment.
 49. A method according to claim 45, wherein said compound isadministered in an amount of 0.01-100 mg/kg of body weight/day.
 50. Amethod according to claim 45, wherein said patient is suffering frommemory impairment due to Alzheimer's disease, schizophrenia, Parkinson'sdisease, Huntington's disease, Pick's disease, Creutzfeld-Jakob disease,depression, aging, head trauma, stroke, CNS hypoxia, cerebral senility,multiinfarct dementia, HIV or cardiovascular disease.
 51. A methodaccording to claim 45, wherein said compound selected from:6-Cyclopropylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine6-Methylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine6-Ethylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-fluorobenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(2,6-difluorobenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(2,3-difluorobenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-propyl 2-trifluoromethylpurine6-Cyclopropylamino-9-cyclopentyl-2-trifluoromethylpurine6-Cyclopropylamino-9-(3,4-dimethoxybenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3,4-methylenedioxybenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-thiophenemethyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(2-methylphenethyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-cyclopropylmethyl-2-trifluoromethylpurine6-Cyclopropylamino-9-cycloheptyl-2-trifluoromethylpurine6-Methylamino-9-cyclopentyl-2-trifluoromethylpurine6-Cyclopropylamino-9-cyclohexyl-2-trifluoromethylpurine6-Methylamino-9-cycloheptyl-2-trifluoromethylpurine6-Cyclopropylamino-9-cyclopentylmethyl-2-trifluoromethylpurine6-Cyclopropylamino-9-phenyl-2-trifluoromethylpurine6-Cyclopropylamino-9-(2-fluorophenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-cyclobutyl-2-trifluoromethylpurine6-Cyclopropylamino-9-(2-norboranane)-2-trifluoromethylpurine6-Cyclopropylamino-9-(1-indanyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-fluorophenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-chlorophenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-tolyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-thienyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-cyclopentyloxy-4-methoxybenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3,4-dimethoxyphenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(2,6-dichloro-4-pyridylmethyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-methoxybenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-methoxyphenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-methoxyphenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-nitrophenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(2-methoxyphenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-cyanophenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(2,4-dimethoxyphenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-nitrobenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(6-methoxy-3-pyridyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-pyridyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-pyridyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-dimethylaminophenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-aminophenyl)-2-trifluoromethylpurine6-Methylamino-9-(2,4-dimethoxy-5-pyrimidyl)-2-trifluoromethylpurine6-Methylamino-9-(2-methoxyphenyl)-2-trifluoromethylpurine6-Methylamino-9-(4-methoxyphenyl)-2-trifluoromethylpurine6-Methylamino-9-(3-acetylphenyl)-2-trifluoromethylpurine6-Methylamino-9-(3-methoxyphenyl)-2-trifluoromethylpurine6-Methylamino-9-(3-nitrophenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-furanyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-ethoxyphenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(2-ethoxyphenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3,4-methylenedioxyphenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-ethoxyphenyl)-2-trifluoromethylpurine6-Methylamino-9-(3,4-dimethoxyphenyl)-2-trifluoromethylpurine; andpharmaceutically acceptable salts thereof.
 52. A method according toclaim 51, wherein said patient is a human.
 53. A method according toclaim 45, wherein when R^(1c) is methyl, then R^(2c) is not arylalkyl,methyl or 2-butyl, and when R^(1c) is H, then R^(2c) is not benzyl
 54. Amethod according to claim 45, wherein: (a) when R^(1c) is methyl, thenR^(2c) is not arylalkyl, heteroarylalkyl,2-(1,2,3,4-tetrahydro)quinolinyl-methyl, methyl or 2-butyl; (b) whenR^(1c) is cyclopropyl, R^(2c) is not 4-methylbenzyl; (c) when R^(1c) isethyl, then R^(2c) is not ethyl, 3-aminobenzyl, 2-thienylmethyl,3-thienylmethyl, or 2-pyridylmethyl; (d) when R^(1c) is cyclopropyl,then R^(2c) is not cyclopropylmethyl; (e) when R^(1c) is H, then R^(2c)is not methyl, ethyl, benzyl, 4-methylbenzyl, or substitutedtetrahydrofuranyl; (f) when R^(1c) is methoxyethyl, then R^(2c) is notbenzyl, 3-dimethylaminobenzyl, or 3-thienylmethyl; (g) when R^(1c) isiso-butyl, then R^(2c) is not benzyl; and (h) when R^(1c) is n-butyl,then R^(2c) is not n-butyl.
 56. A method for treating a patient having adisease involving decreased cAMP levels comprising administering to saidpatient an effective amount of a compound according to formula I^(c):

wherein, R^(1c) is H, alkyl having 1 to 5 carbon atoms, which isunsustituted or substituted one or more times by halogen, hydroxy, orcombinations thereof, and wherein a —CH₂— group can be optionallyreplaced by —O—, —S—, or —NH—, cycloalkyl having 3 to 6 carbon atoms, orcycloalkylalkyl having 4 to 7 C atoms; R^(2c) is alkyl having 1 to 12carbon atoms, which is unsubstituted or substituted one or more times byhalogen, hydroxy, cyano or combinations thereof, wherein one or more—CH₂— groups is each independently optionally replaced by —O—, —S—, or—NH—, and wherein optionally one or more —CH₂CH₂— groups is replaced ineach case by —CH═CH— or —C≡C— alkyl ether having 3 to 12 carbon atoms,cycloalkyl having 3 to 12 carbon atoms, which is unsubstituted orsubstituted one or more times by halogen, C₁₋₄ alkyl, halogenated C₁₋₄alkyl, C₁₋₄ alkoxy, cyano or combinations thereof, cycloalkylalkylhaving 4 to 12 C atoms, which is unsubstituted or substituted one ormore times by C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano,halogen, or combinations thereof, aryl having 6 to 14 carbon atoms,which is unsubstituted or substituted one or more times by halogen, C₁₋₄alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy,cyano, hydroxamic acid, carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof, arylalkyl having 7 to 16 carbon atoms, which isunsubstituted or substituted one or more times by halogen, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy,nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy,cyano, hydroxamic acid, carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof, heteroaryl having 5 to 10 ring atoms in which atleast I ring atom is a heteroatom, which is unsubstituted or substitutedone or more times by halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl,hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl,nitro, oxo, amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy,alkoxycarbonyl, hydroxamic acid, carboxamide, C₁₋₄-alkylthio,C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, or combinations thereof,heteroarylalkyl wherein the heteroaryl portion has 5 to 10 ring atoms inwhich at least 1 ring atom is a heteroatom and the alkyl portion has 1to 3 carbon atoms, the heteroaryl portion is unsubstituted or issubstituted one or more times in by halogen, aryl, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy,cyano, trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid,carboxamide, C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl,or combinations thereof, heterocycle having 5 to 10 ring atoms in whichat least 1 ring atom is a heteroatom, which is unsubstituted or issubstituted one or more times in the by halogen, aryl, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy,cyano, trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, or combinations thereof,heterocycle-alkyl wherein the heterocycle portion has 5 to 10 ring atomsin which at least 1 ring atom is a heteroatom-and the alkyl portion has1 to 3 carbon atoms, the heterocycle portion is nonarmoatic and isunsubstituted or is substituted one or more times in the by halogen,aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy,halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl, nitro, oxo, amino,C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, orcombinations thereof, or carbocycle which is nonaromatic, monocyclic orbicyclic, group having 5 to 14 carbon atoms, which is unsubstituted oris substituted one or more times in the by halogen, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy,nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy,cyano, hydroxamic acid, carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof; and pharmaceutically acceptable salts thereof,with the proviso that said compound is not6-methylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine.
 57. A methodaccording to claim 56, wherein when R^(1c) is methyl, then R^(2c) is notarylalkyl, methyl or 2-butyl, and when R^(1c) is H, then R^(2c) is notbenzyl
 58. A method according to claim 56, wherein: (a) when R^(1c) ismethyl, then R^(2c) is not arylalkyl, heteroarylalkyl,2-(1,2,3,4-tetrahydro)quinolinyl-methyl, methyl or 2-butyl; (b) whenR^(1c) is cyclopropyl, R^(2c) is not 4-methylbenzyl; (c) when R^(1c) isethyl, then R^(2c) is not ethyl, 3-aminobenzyl, 2-thienylmethyl,3-thienylmethyl, or 2-pyridylmethyl; (d) when R^(1c) is cyclopropyl,then R^(2c) is not cyclopropylmethyl; (e) when R^(1c) is H, then R^(2c)is not methyl, ethyl, benzyl, 4-methylbenzyl, or substitutedtetrahydrofuranyl; (f) when R^(1c) is methoxyethyl, then R^(2c) is notbenzyl, 3-dimethylaminobenzyl, or 3-thienylmethyl; (g) when R^(1c) isiso-butyl, then R^(2c) is not benzyl; and (h) when R^(1c) is n-butyl,then R^(2c) is not n-butyl.
 59. A method of inhibiting PDE4 enzymeactivity in a patient comprising administering to said patient aneffective amount of a compound according to formula I^(c):

wherein, R^(1c) is H, alkyl having 1 to 5 carbon atoms, which isunsustituted or substituted one or more times by halogen, hydroxy, orcombinations thereof, and wherein a —CH₂— group can be optionallyreplaced by —O—, —S—, or —NH—, cycloalkyl having 3 to 6 carbon atoms, orcycloalkylalkyl having 4 to 7 C atoms; R^(2c) is alkyl having 1 to 12carbon atoms, which is unsubstituted or substituted one or more times byhalogen, hydroxy, cyano or combinations thereof, wherein one or more—CH₂— groups is each independently optionally replaced by —O—, —S—, or—NH—, and wherein optionally one or more —CH₂CH₂— groups is replaced ineach case by —CH═CH— or —C≡C— alkyl ether having 3 to 12 carbon atoms,cycloalkyl having 3 to 12 carbon atoms, which is unsubstituted orsubstituted one or more times by halogen, C₁₋₄ alkyl, halogenated C₁₋₄alkyl, C₁₋₄ alkoxy, cyano or combinations thereof, cycloalkylalkylhaving 4 to 12 C atoms, which is unsubstituted or substituted one ormore times by C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano,halogen, or combinations thereof, aryl having 6 to 14 carbon atoms,which is unsubstituted or substituted one or more times by halogen, C₁₋₄alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy,cyano, hydroxamic acid, carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof, arylalkyl having 7 to 16 carbon atoms, which isunsubstituted or substituted one or more times by halogen, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy,nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy,cyano, hydroxamic acid, carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof, heteroaryl having 5 to 10 ring atoms in which atleast 1 ring atom is a heteroatom, which is unsubstituted or substitutedone or more times by halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl,hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl,nitro, oxo, amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy,alkoxycarbonyl, hydroxamic acid, carboxamide, C₁₋₄-alkylthio,C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, or combinations thereof,heteroarylalkyl wherein the heteroaryl portion has 5 to 10 ring atoms inwhich at least 1 ring atom is a heteroatom and the alkyl portion has 1to 3 carbon atoms, the heteroaryl portion is unsubstituted or issubstituted one or more times in by halogen, aryl, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy,cyano, trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid,carboxamide, C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, Co ₄-alkylsulphonyl,or combinations thereof, heterocycle having 5 to 10 ring atoms in whichat least 1 ring atom is a heteroatom, which is unsubstituted or issubstituted one or more times in the by halogen, aryl, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy,cyano, trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, or combinations thereof,heterocycle-alkyl wherein the heterocycle portion has 5 to 10 ring atomsin which at least 1 ring atom is a heteroatom and the alkyl portion has1 to 3 carbon atoms, the heterocycle portion is nonarmoatic and isunsubstituted or is substituted one or more times in the by halogen,aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy,halogenated C₁₋₄ alkoxy, cyano, tnfluoromethyl, nitro, oxo, amino,C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, orcombinations thereof, or carbocycle which is nonaromatic, monocyclic orbicyclic, group having 5 to 14 carbon atoms, which is unsubstituted oris substituted one or more times in the by halogen, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy,nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy,cyano, hydroxamic acid, carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof; and pharmaceutically acceptable salts thereof,with the proviso that said compound is not6-methylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine.
 60. A methodaccording to claim 59, wherein when R^(1c) is methyl, then R^(2c) is notarylalkyl, methyl or 2-butyl, and when R^(1c) is H, then R^(2c) is notbenzyl
 61. A method according to claim 59, wherein: (a) when R^(1c) ismethyl, then R^(2c) is not arylalkyl, heteroarylalkyl,2-(1,2,3,4-tetrahydro)quinolinyl-methyl, methyl or 2-butyl; (b) whenR^(1c) is cyclopropyl, R^(2c) is not 4-methylbenzyl; (c) when R^(1c) isethyl, then R^(2c) is not ethyl, 3-aminobenzyl, 2-thienylmethyl,3-thienylmethyl, or 2-pyridylmethyl; (d) when R^(1c) is cyclopropyl,then R^(2c) is not cyclopropylmethyl; (e) when R^(1c) is H, then R^(2c)is not methyl, ethyl, benzyl, 4-methylbenzyl, or substitutedtetrahydrofuranyl; (f) when R^(1c) is methoxyethyl, then R^(2c) is notbenzyl, 3-dimethylaminobenzyl, or 3-thienylmethyl; (g) when R^(1c) isiso-butyl, then R^(2c) is not benzyl; and (h) when R^(1c) is n-butyl,then R^(2c) is not n-butyl.
 62. A pharmaceutical composition comprisinga compound according to claim 1 and a pharmaceutically acceptablecarrier.
 63. A composition according to claim 62, wherein saidcomposition contains 0.1-50 mg of said compound.
 64. A method oftreating a patient suffering from memory impairment due to aneurodegenerative disease comprising administering to said patient aneffective amount of a compound according to formula I^(c):

wherein, R^(1c) is H, alkyl having 1 to 5 carbon atoms, which isunsustituted or substituted one or more times by halogen, hydroxy, orcombinations thereof, and wherein a —CH₂— group can be optionallyreplaced by —O—, —S—, or —NH—, cycloalkyl having 3 to 6 carbon atoms, orcycloalkylalkyl having 4 to 7 C atoms; R^(2c) is alkyl having 1 to 12carbon atoms, which is unsubstituted or substituted one or more times byhalogen, hydroxy, cyano or combinations thereof, wherein one or more—CH₂— groups is each independently optionally replaced by —O—, —S—, or—NH—, and wherein optionally one or more —CH₂CH₂— groups is replaced ineach case by —CH═CH— or —C≡C— alkyl ether having 3 to 12 carbon atoms,cycloalkyl having 3 to 12 carbon atoms, which is unsubstituted orsubstituted one or more times by halogen, C₁₋₄ alkyl, halogenated C₁₋₄alkyl, C₁₋₄ alkoxy, cyano or combinations thereof, cycloalkylalkylhaving 4 to 12 C atoms, which is unsubstituted or substituted one ormore times by C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano,halogen, or combinations thereof, aryl having 6 to 14 carbon atoms,which is unsubstituted or substituted one or more times by halogen, C₁₋₄alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy,cyano, hydroxamic acid, carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof, arylalkyl having 7 to 16 carbon atoms, which isunsubstituted or substituted one or more times by halogen, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy,nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy,cyano, hydroxamic acid, carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl, ;C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof, heteroaryl having 5 to 10 ring atoms in which atleast 1 ring atom is a heteroatom, which is unsubstituted or substitutedone or more times by halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl,hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl,nitro, oxo, amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy,alkoxycarbonyl, hydroxamic acid, carboxamide, C₁₋₄-alkylthio,C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, or combinations thereof,heteroarylalkyl wherein the heteroaryl portion has 5 to 10 ring atoms inwhich at least 1 ring atom is a heteroatom and the alkyl portion has 1to 3 carbon atoms, the heteroaryl portion is unsubstituted or issubstituted one or more times in by halogen, aryl, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy,cyano, trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid,carboxamide, C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl,or combinations thereof, heterocycle having 5 to 10 ring atoms in whichat least 1 ring atom is a heteroatom, which is unsubstituted or issubstituted one or more times in the by halogen, aryl, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy,cyano, trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, or combinations thereof,heterocycle-alkyl wherein the heterocycle portion has 5 to 10 ring atomsin which at least 1 ring atom is a heteroatom and the alkyl portion has1 to 3 carbon atoms, the heterocycle portion is nonarmoatic and isunsubstituted or is substituted one or more times in the by halogen,aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy,halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl, nitro, oxo, amino,C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, orcombinations thereof or carbocycle which is nonaromatic, monocyclic orbicyclic, group having 5 to 14 carbon atoms, which is unsubstituted oris substituted one or more times in the by halogen, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy,nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy,cyano, hydroxamic acid, carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof; and pharmaceutically acceptable salts thereof,with the proviso that said compound is not6-methylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine.
 65. A methodaccording to claim 64, wherein when R^(1c) is methyl, then R^(2c) is notarylalkyl, methyl or 2-butyl, and when R^(1c) is H, then R^(2c) is notbenzyl
 66. A method according to claim 64, wherein: (a) when R^(1c) ismethyl, then R^(2c) is not arylalkyl, heteroarylalkyl,2-(1,2,3,4-tetrahydro)quinolinyl-methyl, methyl or 2-butyl; (b) whenR^(1c) is cyclopropyl, R^(2c) is not 4-methylbenzyl; (c) when R^(1c) isethyl, then R^(2c) is not ethyl, 3-aminobenzyl, 2-thienylmethyl,3-thienylmethyl, or 2-pyridylmethyl; (d) when R^(1c) is cyclopropyl,then R^(2c) is not cyclopropylmethyl; (e) when R^(1c) is H, then R^(2c)is not methyl, ethyl, benzyl, 4-methylbenzyl, or substitutedtetrahydrofuranyl; (f) when R^(1c) is methoxyethyl, then R^(2c) is notbenzyl, 3-dimethylaminobenzyl, or 3-thienylmethyl; (g) when R^(1c) isiso-butyl, then R^(2c) is not benzyl; and (h) when R^(1c) is n-butyl,then R^(2c) is not n-butyl.
 67. A method of treating a patient sufferingfrom memory impairment due to an acute neurodegenerative disordercomprising administering to said patient an effective amount of acompound according to formula I^(c):

wherein, R^(1c) is H, alkyl having 1 to 5 carbon atoms, which isunsustituted or substituted one or more times by halogen, hydroxy, orcombinations thereof, and wherein a —CH₂— group can be optionallyreplaced by —O—, —S—, or —N—H—, cycloalkyl having 3 to 6 carbon atoms,or cycloalkylalkyl having 4 to 7 C atoms; R^(2c) is alkyl having 1 to 12carbon atoms, which is unsubstituted or substituted one or more times byhalogen, hydroxy, cyano or combinations thereof, wherein one or more—CH₂— groups is each independently optionally replaced by —O—, —S—, or—NH—, and wherein optionally one or more —CH₂CH₂— groups is replaced ineach case by —CH═CH— or —C≡C— alkyl ether having 3 to 12 carbon atoms,cycloalkyl having 3 to 12 carbon atoms, which is unsubstituted orsubstituted one or more times by halogen, C₁₋₄ alkyl, halogenated C₁₋₄alkyl, C₁₋₄ alkoxy, cyano or combinations thereof, cycloalkylalkylhaving 4 to 12 C atoms, which is unsubstituted or substituted one ormore times by C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano,halogen, or combinations thereof, aryl having 6 to 14 carbon atoms,which is unsubstituted or substituted one or more times by halogen, C₁₋₄alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy,cyano, hydroxamic acid, carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof, arylalkyl having 7 to 16 carbon atoms, which isunsubstituted or substituted one or more times by halogen, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy,nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy,cyano, hydroxamic acid, carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof, heteroaryl having 5 to 10 ring atoms in which atleast 1 ring atom is a heteroatom, which is unsubstituted or substitutedone or more times by halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl,hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl,nitro, oxo, amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy,alkoxycarbonyl, hydroxamic acid, carboxamide, C₁₋₄-alkylthio,C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, or combinations thereof,heteroarylalkyl wherein the heteroaryl portion has 5 to 10 ring atoms inwhich at least 1 ring atom is a heteroatom and the alkyl portion has 1to 3 carbon atoms, the heteroaryl portion is unsubstituted or issubstituted one or more times in by halogen, aryl, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy,cyano, trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid,carboxamide, C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl,or combinations thereof, heterocycle having 5 to 10 ring atoms in whichat least 1 ring atom is a heteroatom, which is unsubstituted or issubstituted one or more times in the by halogen, aryl, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy,cyano, trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, or combinations thereof,heterocycle-alkyl wherein the heterocycle portion has 5 to 10 ring atomsin which at least 1 ring atom is a heteroatom and the alkyl portion has1 to 3 carbon atoms, the heterocycle portion is nonarmoatic and isunsubstituted or is substituted one or more times in the by halogen,aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy,halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl, nitro, oxo, amino,C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, orcombinations thereof, or carbocycle which is nonaromatic, monocyclic orbicyclic, group having 5 to 14 carbon atoms, which is unsubstituted oris substituted one or more times in the by halogen, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy,nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy,cyano, hydroxamic acid, carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof; and pharmaceutically acceptable salts thereof,with the proviso that said compound is not6-methylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine.
 68. A methodaccording to claim 67, wherein when R^(1c) is methyl, then R^(2c) is notarylalkyl, methyl or 2-butyl, and when R^(1c) is H, then R^(2c) is notbenzyl
 69. A method according to claim 67, wherein: (a) when R^(1c) ismethyl, then R^(2c) is not arylalkyl, heteroarylalkyl,2-(1,2,3,4-tetrahydro)quinolinyl-methyl, methyl or 2-butyl; (b) whenR^(1c) is cyclopropyl, R^(2c) is not 4-methylbenzyl; (c) when R^(1c) isethyl, then R^(2c) is not ethyl, 3-aminobenzyl, 2-thienylmethyl,3-thienylmethyl, or 2-pyridylmethyl; (d) when R^(1c) is cyclopropyl,then R^(2c) is not cyclopropylmethyl; (e) when R^(1c) is H, then R^(2c)is not methyl, ethyl, benzyl, 4-methylbenzyl, or substitutedtetrahydrofuranyl; (f) when R^(1c) is methoxyethyl, then R^(2c) is notbenzyl, 3-dimethylaminobenzyl, or 3-thienylmethyl; (g) when R^(1c) isiso-butyl, then R^(2c) is not benzyl; and (h) when R^(1c) is n-butyl,then R^(2c) is not n-butyl.
 70. A method of treating a patient sufferingfrom an allergic or inflammatory disease comprising administering tosaid patient an effective amount of a compound according to formulaI^(c):

wherein, R^(1c) is H, alkyl having 1 to 5 carbon atoms, which isunsustituted or substituted one or more times by halogen, hydroxy, orcombinations thereof, and wherein a —CH₂— group can be optionallyreplaced by —O—, —S—, or —NH—, cycloalkyl having 3 to 6 carbon atoms, orcycloalkylalkyl having 4 to 7 C atoms; R^(2c) is alkyl having 1 to 12carbon atoms, which is unsubstituted or substituted one or more times byhalogen, hydroxy, cyano or combinations thereof, wherein one or more—CH₂— groups is each independently optionally replaced by —O—, —S—, or—NH—, and wherein optionally one or more —CH₂CH₂— groups is replaced ineach case by-CH═CH— or —C≡C— alkyl ether having 3 to 12 carbon atoms,cycloalkyl having 3 to 12 carbon atoms, which is unsubstituted orsubstituted one or more times by halogen, C₁₋₄ alkyl, halogenated C₁₋₄alkyl, C₁₋₄ alkoxy, cyano or combinations thereof, cycloalkylalkylhaving 4 to 12 C atoms, which is unsubstituted or substituted one ormore times by C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano,halogen, or combinations thereof, aryl having 6 to 14 carbon atoms,which is unsubstituted or substituted one or more times by halogen, C₁₋₄alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy,cyano, hydroxamic acid, carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof, arylalkyl having 7 to 16 carbon atoms, which isunsubstituted or substituted one or more times by halogen, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy,nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy,cyano, hydroxamic acid, carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof, heteroaryl having 5 to 10 ring atoms in which atleast 1 ring atom is a heteroatom, which is unsubstituted or substitutedone or more times by halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl,hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl,nitro, oxo, amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy,alkoxycarbonyl, hydroxamic acid, carboxamide, C₁₋₄-alkylthio,C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, or combinations thereof,heteroarylalkyl wherein the heteroaryl portion has 5 to 10 ring atoms inwhich at least 1 ring atom is a heteroatom and the alkyl portion has 1to 3 carbon atoms, the heteroaryl portion is unsubstituted or issubstituted one or more times in by halogen, aryl, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy,cyano, trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid,carboxamide, C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl,or combinations thereof, heterocycle having 5 to 10 ring atoms in whichat least 1 ring atom is a heteroatom, which is unsubstituted or issubstituted one or more times in the by halogen, aryl, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy,cyano, trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, or combinations thereof,heterocycle-alkyl wherein the heterocycle portion has 5 to 10 ring atomsin which at least 1 ring atom is a heteroatom and the alkyl portion has1 to 3 carbon atoms, the heterocycle portion is nonarmoatic and isunsubstituted or is substituted one or more times in the by halogen,aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy,halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl, nitro, oxo, amino,C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, orcombinations thereof, or carbocycle which is nonaromatic, monocyclic orbicyclic, group having 5 to
 14. carbon atoms, which is unsubstituted oris substituted one or more times in the by halogen, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy,nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy,cyano, hydroxamic acid, carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof; and pharmaceutically acceptable salts thereof,with the proviso that said compound is not6-methylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine.
 71. A methodaccording to claim 70, wherein when R^(1c) is methyl, then R^(2c) is notarylalkyl, methyl or 2-butyl, and when R^(1c) is H, then R^(2c) is notbenzyl
 72. A method according to claim 70, wherein: (a) when R^(1c) ismethyl, then R^(2c) is not arylalkyl, heteroarylalkyl,2-(1,2,3,4-tetrahydro)quinolinyl-methyl, methyl or 2-butyl, (b) whenR^(1c) is cyclopropyl, R^(2c) is not 4-methylbenzyl; (c) when R^(1c) isethyl, then R^(2c) is not ethyl, 3-aminobenzyl, 2-thienylmethyl,3-thienylmethyl, or 2-pyridylmethyl; (d) when R^(1c) is cyclopropyl,then R^(2c) is not cyclopropylmethyl; (e) when R^(1c) is H, then R^(2c)is not methyl, ethyl, benzyl, 4-methylbenzyl, or substitutedtetrahydrofuranyl; (f) when R^(1c) is methoxyethyl, then R^(2c) is notbenzyl, 3-dimethylaminobenzyl, or 3-thienylmethyl; (g) when R^(1c) isiso-butyl, then R^(2c) is not benzyl; and (h) when R^(1c) is n-butyl,then R^(2c) is not n-butyl.
 73. A process for preparing compounds of theformula IV

wherein R¹ is H, alkyl having 1 to 5 carbon atoms, which is unsustitutedor substituted one or more times by halogen, hydroxy, or combinationsthereof, and wherein a —CH₂— group can be optionally replaced by —O—,—S—, or —NH—, cycloalkyl having 3 to 6 carbon atoms, or cycloalkylalkylhaving 4 to 7 C atoms; and R² is aryl having 6 to 14 carbon atoms, whichis unsubstituted or substituted one or more times by halogen, C₁₋₄alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, T 1S halogenatedC₁₋₄ alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄alkylamino, di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy,carboxy, cyano, hydroxamic acid, carboxamide, C₂₋₄-acyl,C₂₋₄-alkoxycarbonyl, C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl,C₁₋₄-alkylsulphonyl, phenoxy, or combinations thereof, heteroaryl having5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, whichis unsubstituted or substituted one or more times by halogen, aryl, C₁₋₄alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid,carboxamide, C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl,or combinations thereof, said process comprising: reacting6-N—R¹-substituted adenine with an arylboronic acid or heteroarylboronicacid in the presence of trialkylamine wherein the alkyl have 1 to 5 Catoms, e.g., triethylamine, as a base, a copper catalyst, and a polaraprotic solvent, for example THF and CH₃CN (particulary, CH₃CN) at atemperature of at least 50° C., e.g., 50-60° C.
 74. A compound accordingto claim 1, wherein R² is cycloalkylalkyl.
 75. compound according toclaim 74 wherein R¹ is alkyl, cycloalkyl or cycloalkylalkyl.